Physicians’ attitudes toward pharmacogenetic testing before and after pharmacogenetic education

PubMed Central

Luzum, Jasmine A; Luzum, Matthew J

2016-01-01

Aim: Our aim was to evaluate physicians’ attitudes toward pharmacogenetic testing before and after pharmacogenetic education. Methods: In total, 12 physicians (˜40% response rate) completed a survey with eight questions on 10-point scales on their attitudes toward pharmacogenetic testing before and after a 1-h grand rounds presentation on pharmacogenetics. Differences in question scores overall, among training levels (resident/fellow/attending), and specific drugs (clopidogrel/simvastatin/warfarin) were assessed using Wilcoxon signed-rank and exact Kruskal–Wallis tests. Results & conclusion: The scores for all eight questions increased, with statistically significant (p < 0.05) increases for four out of eight questions. The scores were similar among training levels, but the postscores for clopidogrel were significantly higher than for simvastatin and warfarin. In conclusion, brief pharmacogenetic education can significantly affect physicians’ attitudes toward pharmacogenetic testing. PMID:29749904

Pharmacogenetics and rational drug use around the world.

PubMed

Roederer, Mary W; Sanchez-Giron, Francisco; Kalideen, Kusha; Kudzi, William; McLeod, Howard L; Zhang, Wei

2011-06-01

The WHO embraces evidence-based medicine to formulate an essential medicines list (EML) considering disease prevalence, drug efficacy, drug safety and cost-effectiveness. The EML is used by developing countries to build a national formulary. As pharmacogenetics in developed countries evolves, the Pharmacogenetics for Every Nation Initiative (PGENI) convened with representatives from China, Mexico, Ghana and South Africa in August 2009 to evaluate the use of human pharmacogenetics to enhance global drug use policy. The diseases causing mortality, the lack of integration of pharmacovigilance at the national formulary level, the pharmacogenetics research agenda and pharmacogenetics clinician education did not differ greatly among the countries. While there are many unanswered questions, systematically incorporating pharmacogenetics at the national formulary level promises to improve global drug use.

A Pharmacogenetics Service Experience for Pharmacy Students, Residents, and Fellows

PubMed Central

Drozda, Katarzyna; Labinov, Yana; Jiang, Ruixuan; Thomas, Margaret R.; Wong, Shan S.; Patel, Shitalben; Nutescu, Edith A.

2013-01-01

Objective. To utilize a comprehensive, pharmacist-led warfarin pharmacogenetics service to provide pharmacy students, residents, and fellows with clinical and research experiences involving genotype-guided therapy. Design. First-year (P1) through fourth-year (P4) pharmacy students, pharmacy residents, and pharmacy fellows participated in a newly implemented warfarin pharmacogenetics service in a hospital setting. Students, residents, and fellows provided genotype-guided dosing recommendations as part of clinical care, or analyzed samples and data collected from patients on the service for research purposes. Assessment. Students’, residents’, and fellows’ achievement of learning objectives was assessed using a checklist based on established core competencies in pharmacogenetics. The mean competency score of the students, residents, and fellows who completed a clinical and/or research experience with the service was 97% ±3%. Conclusion. A comprehensive warfarin pharmacogenetics service provided unique experiential and research opportunities for pharmacy students, residents, and fellows and sufficiently addressed a number of core competencies in pharmacogenetics. PMID:24159216

A pharmacogenetics service experience for pharmacy students, residents, and fellows.

PubMed

Drozda, Katarzyna; Labinov, Yana; Jiang, Ruixuan; Thomas, Margaret R; Wong, Shan S; Patel, Shitalben; Nutescu, Edith A; Cavallari, Larisa H

2013-10-14

To utilize a comprehensive, pharmacist-led warfarin pharmacogenetics service to provide pharmacy students, residents, and fellows with clinical and research experiences involving genotype-guided therapy. First-year (P1) through fourth-year (P4) pharmacy students, pharmacy residents, and pharmacy fellows participated in a newly implemented warfarin pharmacogenetics service in a hospital setting. Students, residents, and fellows provided genotype-guided dosing recommendations as part of clinical care, or analyzed samples and data collected from patients on the service for research purposes. Students', residents', and fellows' achievement of learning objectives was assessed using a checklist based on established core competencies in pharmacogenetics. The mean competency score of the students, residents, and fellows who completed a clinical and/or research experience with the service was 97% ±3%. A comprehensive warfarin pharmacogenetics service provided unique experiential and research opportunities for pharmacy students, residents, and fellows and sufficiently addressed a number of core competencies in pharmacogenetics.

Pharmacogenetics in Latin American populations: regulatory aspects, application to herbal medicine, cardiovascular and psychiatric disorders.

PubMed

Rodeiro, Idania; Remírez-Figueredo, Diadelis; García-Mesa, Milagros; Dorado, Pedro; LLerena, Adrián

2012-01-01

Meeting report of the "Second Symposium on Pharmacology of Cytochrome P450 and Transporters" organized by the Cuban Society of Pharmacology in collaboration with the European Society of Pharmacogenetics and Theranostics (ESPT) and the Ibero-American Network of Pharmacogenetics and Pharmacogenomics (www.ribef.com). The Symposium covered different topics on pharmacogenetics and its clinical implications, focusing on Latin-American populations. The activities of the ESPT were also presented and discussed. The topics addressed were regulatory aspects, the use of pharmacogenetics in pre-clinical research, herbal medicine, and natural products, ending with a discussion about translation into clinical practice, specifically for cardiovascular disorders and psychiatry. Finally, the implication for population diversity in Latin America was also discussed. The RIBEF initiative represents a promising step towards the inclusion of Latin American populations among those to benefit from the implementation of pharmacogenetics in clinical practice. Among current RIBEF activities, the CEIBA.FP Consortium aims to study the variability of pheno- and genotypes in Hispanics that are relevant to pharmacogenetics. For this purpose, populations from Mexico, Cuba, Nicaragua, Costa Rica, Ecuador, Colombia, Brasil, Perú, Chile, Uruguay, Argentina, Portugal, and Spain are currently being studied. The meeting's main conclusion was that population pharmacogenetic studies as well as academic clinical trials might need to be conducted in the different geographic locations/countries. This is important in order to improve drug safety, dosage recommendations, and pharmacovigilance programs, because environmental and ethnic factors vary across locations.

Pharmacogenetics in Cardiovascular Medicine

PubMed Central

Tuteja, Sony; Limdi, Nita

2017-01-01

Purpose of review Pharmacogenetics is an important component of precision medicine. Even within the genomic era, several challenges lie ahead in the road towards clinical implementation of pharmacogenetics in the clinic. This review will summarize the current state of knowledge regarding pharmacogenetics of cardiovascular drugs, focusing on those with the most evidence supporting clinical implementation- clopidogrel, warfarin and simvastatin. Recent findings There is limited translation of pharmacogenetics into clinical practice primarily due to the absence of outcomes data from prospective, randomized, genotype-directed clinical trials. There are several ongoing randomized controlled trials that will provide some answers as to the clinical utility of genotype-directed strategies. Several academic medical centers have pushed towards clinical implementation where the clinical validity data are strong. Their experiences will inform operational requirements of a clinical pharmacogenetics testing including the timing of testing, incorporation of test results into the electronic health record, reimbursement and ethical issues. Summary Pharmacogenetics of clopidogrel, warfarin and simvastatin are three examples where pharmacogenetics testing may provide added clinical value. Continued accumulation of evidence surrounding clinical utility of pharmacogenetics markers is imperative as this will inform reimbursement policy and drive adoption of pharamcogenetics into routine care. PMID:29057167

Pharmacogenetic studies in Alzheimer disease.

PubMed

Zúñiga Santamaría, T; Yescas Gómez, P; Fricke Galindo, I; González González, M; Ortega Vázquez, A; López López, M

2018-06-10

Alzheimer disease (AD) is the most common cause of dementia and is considered one of the main causes of disability and dependence affecting quality of life in elderly people and their families. Current pharmacological treatment includes acetylcholinesterase inhibitors (donepezil, galantamine, rivastigmine) and memantine; however, only one-third of patients respond to treatment. Genetic factors have been shown to play a role in this inter-individual variability in drug response. We review pharmacogenetic reports of AD-modifying drugs, the pharmacogenetic biomarkers included, and the phenotypes evaluated. We also discuss relevant methodological considerations for the design of pharmacogenetic studies into AD. A total of 33 pharmacogenetic reports were found; the majority of these focused on the variability in response to and metabolism of donepezil. Most of the patients included were from Caucasian populations, although some studies also include Korean, Indian, and Brazilian patients. CYP2D6 and APOE are the most frequently studied biomarkers. The associations proposed are controversial. Potential pharmacogenetic biomarkers for AD have been identified; however, it is still necessary to conduct further research into other populations and to identify new biomarkers. This information could assist in predicting patient response to these drugs and contribute to better treatment decision-making in a context as complex as aging. Copyright © 2018 Sociedad Española de Neurología. Publicado por Elsevier España, S.L.U. All rights reserved.

Systems pharmacology, pharmacogenetics, and clinical trial design in network medicine.

PubMed

Antman, Elliott; Weiss, Scott; Loscalzo, Joseph

2012-01-01

The rapidly growing disciplines of systems biology and network science are now poised to meet the fields of clinical medicine and pharmacology. Principles of systems pharmacology can be applied to drug design and, ultimately, testing in human clinical trials. Rather than focusing exclusively on single drug targets, systems pharmacology examines the holistic response of a phenotype-dependent pathway or pathways to drug perturbation. Knowledge of individual pharmacogenetic profiles further modulates the responses to these drug perturbations, moving the field toward more individualized ('personalized') drug development. The speed with which the information required to assess these system responses and their genomic underpinnings is changing and the importance of identifying the optimal drug or drug combinations for maximal benefit and minimal risk require that clinical trial design strategies be adaptable. In this paper, we review the tenets of adaptive clinical trial design as they may apply to an era of expanding knowledge of systems pharmacology and pharmacogenomics, and clinical trail design in network medicine. Copyright © 2012 Wiley Periodicals, Inc.

Pharmacogenetically driven treatments for alcoholism: are we there yet?

PubMed

Arias, Albert J; Sewell, R Andrew

2012-06-01

Pharmacogenetic analyses of treatments for alcohol dependence attempt to predict treatment response and side-effect risk for specific medications. We review the literature on pharmacogenetics relevant to alcohol dependence treatment, and describe state-of-the-art methods of pharmacogenetic research in this area. Two main pharmacogenetic study designs predominate: challenge studies and treatment-trial analyses. Medications studied include US FDA-approved naltrexone and acamprosate, both indicated for treating alcohol dependence, as well as several investigational (and off-label) treatments such as sertraline, olanzapine and ondansetron. The best-studied functional genetic variant relevant to alcoholism treatment is rs1799971, a single-nucleotide polymorphism in exon 1 of the OPRM1 gene that encodes the μ-opioid receptor. Evidence from clinical trials suggests that the presence of the variant G allele of rs1799971 may predict better treatment response to opioid receptor antagonists such as naltrexone. Evidence from clinical trials also suggests that several medications interact pharmacogenetically with variation in genes that encode proteins involved in dopaminergic and serotonergic neurotransmission. Variation in the DRD4 gene, which encodes the dopamine D(4) receptor, may predict better response to naltrexone and olanzapine. A polymorphism in the serotonin transporter gene SLC6A4 promoter region appears related to differential treatment response to sertraline depending on the subject's age of onset of alcoholism. Genetic variation in SLC6A4 may also be associated with better treatment response to ondansetron. Initial pharmacogenetic efforts in alcohol research have identified functional variants with potential clinical utility, but more research is needed to further elucidate the mechanism of these pharmacogenetic interactions and their moderators in order to translate them into clinical practice.

Pharmacogenetics, ethical issues: review of the Nuffield Council on Bioethics Report

PubMed Central

Corrigan, O

2005-01-01

In September this year the Nuffield Council on Bioethics held a meeting to disclose and discuss the main findings of their newly published report on the ethical issues associated with developments in pharmacogenetics research. The basics of pharmacogenetics science is briefly outlined, and then the extent to which the report was successful in addressing (or at least highlighting) the attendant social, ethical, and policy implications of pharmacogenetics research is evaluated. PMID:15738433

Progress in pharmacogenetics: consortiums and new strategies.

PubMed

Maroñas, Olalla; Latorre, Ana; Dopazo, Joaquín; Pirmohamed, Munir; Rodríguez-Antona, Cristina; Siest, Gérard; Carracedo, Ángel; LLerena, Adrián

2016-03-01

Pharmacogenetics (PGx), as a field dedicated to achieving the goal of personalized medicine (PM), is devoted to the study of genes involved in inter-individual response to drugs. Due to its nature, PGx requires access to large samples; therefore, in order to progress, the formation of collaborative consortia seems to be crucial. Some examples of this collective effort are the European Society of Pharmacogenomics and personalized Therapy and the Ibero-American network of Pharmacogenetics. As an emerging field, one of the major challenges that PGx faces is translating their discoveries from research bench to bedside. The development of genomic high-throughput technologies is generating a revolution and offers the possibility of producing vast amounts of genome-wide single nucleotide polymorphisms for each patient. Moreover, there is a need of identifying and replicating associations of new biomarkers, and, in addition, a greater effort must be invested in developing regulatory organizations to accomplish a correct standardization. In this review, we outline the current progress in PGx using examples to highlight both the importance of polymorphisms and the research strategies for their detection. These concepts need to be applied together with a proper dissemination of knowledge to improve clinician and patient understanding, in a multidisciplinary team-based approach.

Personalizing medicine with clinical pharmacogenetics

PubMed Central

Scott, Stuart A.

2012-01-01

Clinical genetic testing has grown substantially over the past 30 years as the causative mutations for Mendelian diseases have been identified, particularly aided in part by the recent advances in molecular-based technologies. Importantly, the adoption of new tests and testing strategies (e.g., diagnostic confirmation, prenatal testing, and population-based carrier screening) has often been met with caution and careful consideration before clinical implementation, which facilitates the appropriate use of new genetic tests. Although the field of pharmacogenetics was established in the 1950s, clinical testing for constitutional pharmacogenetic variants implicated in interindividual drug response variability has only recently become available to help clinicians guide pharmacotherapy, in part due to US Food and Drug Administration-mediated product insert revisions that include pharmacogenetic information for selected drugs. However, despite pharmacogenetic associations with adverse outcomes, physician uptake of clinical pharmacogenetic testing has been slow. Compared with testing for Mendelian diseases, pharmacogenetic testing for certain indications can have a lower positive predictive value, which is one reason for underutilization. A number of other barriers remain with implementing clinical pharmacogenetics, including clinical utility, professional education, and regulatory and reimbursement issues, among others. This review presents some of the current opportunities and challenges with implementing clinical pharmacogenetic testing. PMID:22095251

Development and Implementation of a Pharmacist-Managed Clinical Pharmacogenetics Service

PubMed Central

Crews, Kristine R.; Cross, Shane J.; McCormick, John N.; Baker, Donald K.; Molinelli, Alejandro R.; Mullins, Richard; Relling, Mary V.; Hoffman, James M.

2011-01-01

Purpose The development and implementation of a pharmacist-managed Clinical Pharmacogenetics service is described. Summary Therapeutic drug monitoring (TDM) is a well-accepted role of the pharmacist. Pharmacogenetics, the study of genetic factors that influence the variability in drug response among patients, is a rapidly evolving discipline that integrates knowledge of pharmacokinetics and pharmacodynamics with modern advances in genetic testing. There is growing evidence for the clinical utility of pharmacogenetics, and pharmacists can play an essential role in the thoughtful application of pharmacogenetics to patient care. A pharmacist-managed Clinical Pharmacogenetics service was designed and implemented. The goal of the service is to provide clinical pharmacogenetic testing for gene products important to the pharmacodynamics of medications used in our patients. The service is modeled after and integrated with an already established Clinical Pharmacokinetics service. All clinical pharmacogenetic test results are first reported to one of the pharmacists, who reviews the result and provides a written consult. The consult includes an interpretation of the result and recommendations for any indicated changes to therapy. In 2009, 136 clinical pharmacogenetic tests were performed, consisting of 66 TPMT tests, 65 CYP2D6 tests, and 5 UGT1A1 tests. Our service has been met with positive clinician feedback. Conclusion Our experience demonstrates the feasibility of the design and function of a pharmacist-managed Clinical Pharmacogenetics service at an academic specialty hospital. The successful implementation of this service highlights the leadership role that pharmacists can take in moving pharmacogenetics from research to patient care, thereby potentially improving patient outcomes. PMID:21200062

Reprogenetics and pharmacogenetics: in whose best interests?

PubMed

Mackenzie, Robin

2005-06-01

Reprogenetics involves embryonic pre-implantation genetic diagnosis, provoking controversy over the creation of saviour siblings, eugenics and genetic enhancement. It will soon ascertain pharmacogenetic susceptibilities. Pharmacogenetics impacts upon public health initiatives underpinned by resource allocation constraints in that genetic epidemiological studies assist in administering health care resources and public health strategies. Knowing how likely sections of the population are to develop specific medical conditions so that lifestyle and environmental factors influencing these conditions can be targeted has the potential to save public money and improve public health. Aligning population groups with genetic susceptibilities with specific medications would enable cost-effective prescribing. Reprogenetics and pharmacogenetics also possess great commercial potential for nation states and biotechnology companies. Hence ethical legal safeguards for members of the public whose reproductive or genetic tissue is a research or health care resource are essential. Both legal measures such as informed consent and mechanisms for including the public in policy decisions over reprogenetics and pharmacogenetics must be rethought to ensure that they provide protection rather than function as rubber stamps which preclude deeper inquiry into justifications of projects.

Pharmacogenetic testing through the direct-to-consumer genetic testing company 23andMe.

PubMed

Lu, Mengfei; Lewis, Cathryn M; Traylor, Matthew

2017-06-19

Rapid advances in scientific research have led to an increase in public awareness of genetic testing and pharmacogenetics. Direct-to-consumer (DTC) genetic testing companies, such as 23andMe, allow consumers to access their genetic information directly through an online service without the involvement of healthcare professionals. Here, we evaluate the clinical relevance of pharmacogenetic tests reported by 23andMe in their UK tests. The research papers listed under each 23andMe report were evaluated, extracting information on effect size, sample size and ethnicity. A wider literature search was performed to provide a fuller assessment of the pharmacogenetic test and variants were matched to FDA recommendations. Additional evidence from CPIC guidelines, PharmGKB, and Dutch Pharmacogenetics Working Group was reviewed to determine current clinical practice. The value of the tests across ethnic groups was determined, including information on linkage disequilibrium between the tested SNP and causal pharmacogenetic variant, where relevant. 23andMe offers 12 pharmacogenetic tests to their UK customers, some of which are in standard clinical practice, and others which are less widely applied. The clinical validity and clinical utility varies extensively between tests. The variants tested are likely to have different degrees of sensitivity due to different risk allele frequencies and linkage disequilibrium patterns across populations. The clinical relevance depends on the ethnicity of the individual and variability of pharmacogenetic markers. Further research is required to determine causal variants and provide more complete assessment of drug response and side effects. 23andMe reports provide some useful pharmacogenetics information, mirroring clinical tests that are in standard use. Other tests are unspecific, providing limited guidance and may not be useful for patients without professional interpretation. Nevertheless, DTC companies like 23andMe act as a powerful

The pharmacogenetics of alcohol use disorder.

PubMed

Jones, Jermaine D; Comer, Sandra D; Kranzler, Henry R

2015-03-01

Annually, the use and abuse of alcohol contributes to millions of deaths and billions of dollars in societal costs. To determine the impact of genetic variation on the susceptibility to the disorder and its response to treatment, studies have been conducted to assess the contribution of a variety of candidate genetic variants. These variants, which we review here, were chosen based upon their observed or hypothesized functional relevance to alcohol use disorder (AUD) risk or to the mechanism by which medications used to treat the disorder exert their effects. This qualitative review examines studies in which candidate polymorphisms were tested as moderator variables to identify pharmacogenetic effects on either the subjective response to alcohol or the outcomes of pharmacotherapy. Although findings from these studies provide evidence of a number of clinically relevant pharmacogenetic effects, the literature is limited and there are conflicting findings that require resolution. Pharmacogenetic studies of AUD treatment that use greater methodological rigor and better statistical controls, such as corrections for multiple testing, may help to resolve inconsistent findings. These procedures could also lead to the discovery of more robust and clinically meaningful moderator effects. As the field evolves through methodological standardization and the use of larger study samples, pharmacogenetic research has the potential to inform clinical care by enhancing therapeutic effects and personalizing treatments. These efforts may also provide insights into the mechanisms by which medications reduce heavy drinking or promote abstinence in patients with an AUD. Copyright © 2015 by the Research Society on Alcoholism.

Implementation of pharmacogenetics: the University of Maryland Personalized Anti-platelet Pharmacogenetics Program.

PubMed

Shuldiner, Alan R; Palmer, Kathleen; Pakyz, Ruth E; Alestock, Tameka D; Maloney, Kristin A; O'Neill, Courtney; Bhatty, Shaun; Schub, Jamie; Overby, Casey Lynnette; Horenstein, Richard B; Pollin, Toni I; Kelemen, Mark D; Beitelshees, Amber L; Robinson, Shawn W; Blitzer, Miriam G; McArdle, Patrick F; Brown, Lawrence; Jeng, Linda Jo Bone; Zhao, Richard Y; Ambulos, Nicholas; Vesely, Mark R

2014-03-01

Despite a substantial evidence base, implementation of pharmacogenetics into routine patient care has been slow due to a number of non-trivial practical barriers. We implemented a Personalized Anti-platelet Pharmacogenetics Program (PAP3) for cardiac catheterization patients at the University of Maryland Medical Center and the Baltimore Veterans Administration Medical Center Patients' are offered CYP2C19 genetic testing, which is performed in our Clinical Laboratory Improvement Amendment (CLIA)-certified Translational Genomics Laboratory. Results are returned within 5 hr along with clinical decision support that includes interpretation of results and prescribing recommendations for anti-platelet therapy based on the Clinical Pharmacogenetics Implementation Consortium guidelines. Now with a working template for PAP3, implementation of other drug-gene pairs is in process. Lessons learned as described in this article may prove useful to other medical centers as they implement pharmacogenetics into patient care, a critical step in the pathway to personalized and genomic medicine. © 2014 Wiley Periodicals, Inc.

IMPLEMENTATION OF PHARMACOGENETICS: THE UNIVERSITY OF MARYLAND PERSONALIZED ANTI-PLATELET PHARMACOGENETICS PROGRAM

PubMed Central

Shuldiner, Alan R.; Palmer, Kathleen; Pakyz, Ruth E.; Alestock, Tameka D.; Maloney, Kristin A.; O’Neill, Courtney; Bhatty, Shaun; Schub, Jamie; Overby, Casey Lynnette; Horenstein, Richard B.; Pollin, Toni I.; Kelemen, Mark D.; Beitelshees, Amber L.; Robinson, Shawn W.; Blitzer, Miriam G.; McArdle, Patrick F.; Brown, Lawrence; Jeng, Linda Jo Bone; Zhao, Richard Y.; Ambulos, Nicholas; Vesely, Mark R.

2014-01-01

Despite a substantial evidence base, implementation of pharmacogenetics into routine patient care has been slow due to a number of non-trivial practical barriers. We implemented a Personalized Anti-platelet Pharmacogenetics Program (PAP3) for cardiac catheterization patients at the University of Maryland Medical Center and the Baltimore Veterans Administration Medical Center Patients are offered CYP2C19 genetic testing, which is performed in our Clinical Laboratory Improvement Amendment (CLIA)-certified Translational Genomics Laboratory. Results are returned within five hours along with clinical decision support that includes interpretation of results and prescribing recommendations for anti-platelet therapy based on the Clinical Pharmacogenetics Implementation Consortium guidelines. Now with a working template for PAP3, implementation of other drug-gene pairs is in process. Lessons learned as described in this article may prove useful to other medical centers as they implement pharmacogenetics into patient care, a critical step in the pathway to personalized and genomic medicine. PMID:24616408

Pharmacogenetics of immunosuppressants: State of the art and clinical implementation - recommendations from the French National Network of Pharmacogenetics (RNPGx).

PubMed

Woillard, Jean-Baptiste; Chouchana, Laurent; Picard, Nicolas; Loriot, Marie-Anne

2017-04-01

Therapeutic drug monitoring is already widely used for immunosuppressive drugs due to their narrow therapeutic index. This article summarizes evidence reported in the literature regarding the pharmacogenetics of (i) immunosuppressive drugs used in transplantation and (ii) azathioprine used in chronic inflammatory bowel disease. The conditions of use of currently available major pharmacogenetic tests are detailed and recommendations are provided based on a scale established by the RNPGx scoring tests as "essential", "advisable" and "potentially useful". Other applications for which the level of evidence is still debated are also discussed. Copyright © 2017 Société française de pharmacologie et de thérapeutique. Published by Elsevier Masson SAS. All rights reserved.

Evidence-based pharmacogenetics: Is it possible?

PubMed

Sychev, D A; Malova, E U

2015-01-01

For improving quality, safety and efficiency of care, health systems perform a paradigm change towards personalized medicine, also referred to as genomic medicine. It uses combined knowledge (genomics, transcriptomics, proteomics, metabolomics) about a person to predict disease susceptibility, disease prognosis or treatment response and thereby to improve the person's health. The last decade has witnessed a steady embrace of personalized medicine by senior government officials, industry leadership and health care providers [1]. On the 12th December of 2013 Russian President Vladimir Putin in his annual address to the Federal Assembly said: "The Ministry of Health and the Russian Academy of Sciences must give priority to fundamental and applied research in medicine, including genomic studies" [2]. A year earlier, in 2012 the Ministry of Health of the Russian Federation, headed by Veronika Skvortsova established the strategy of personalized medicine development in Russia [3]. But still a lot of work is focused on using clinical research findings to aid the delivery of optimum clinical care to patients. Pharmacogenetic testing (using genetic information to guide drug therapy) is an actively developing field of personalized medicine and its current state indicates that it can be usefully introduced into clinical practice in the nearest future. In Russia pharmacogenetic testing is already used for personalizing prescription of certain drugs [4]. To assess the extent of genetic testing use for improving use of medicines. PubMed and E-Library searches for the period of 2004-2015. The number of publications retrieved in PubMed search for the term "pharmacogenetics" for 2004 year was 538 and was more than 15500 publications for 2015. 800 Russian-language publications in total were retrieved using a domestic scientific database E-Library search for the term "pharmacogenetics" for 2015 year. The sharp rise in the number of publications (including Russia) reflects growing

Pharmacogenetics in drug regulation: promise, potential and pitfalls

PubMed Central

Shah, Rashmi R

2005-01-01

result in complex prescribing information. Genotype-specific dosing regimens will have to be more precise and marketing strategies more prudent. However, not all variations in drug responses are related to pharmacogenetic polymorphisms. Drug response can be modulated by a number of non-genetic factors, especially co-medications and presence of concurrent diseases. Inappropriate prescribing frequently compounds the complexity introduced by these two important non-genetic factors. Unless prescribers adhere to the prescribing information, much of the benefits of pharmacogenetics will be squandered. Discovering highly predictive genotype–phenotype associations during drug development and demonstrating their clinical validity and utility in well-designed prospective clinical trials will no doubt better define the role of pharmacogenetics in future clinical practice. In the meantime, prescribing should comply with the information provided while pharmacogenetic research is deservedly supported by all concerned but without unrealistic expectations. PMID:16096112

[Pharmacogenetics in primary health care: implementation and future expectations].

PubMed

Houwink, Elisa J F; Rigter, Tessel; Swen, Jesse J; Cornel, Martina C; Kienhuis, Anne; Rodenburg, Wendy; Weda, Marjolein

2015-01-01

Personalised medicine is a targeted approach to the prevention, diagnosis and treatment of disorders on the basis of the specific genetic profile of the patient. Pharmacogenetics research shows that differences in the genetic profile of patients explain the interindividual differences in efficacy and side effects of medicines. Although there are high expectations of personalised medicine and pharmacogenetics in healthcare, both are only used to a limited extent to date. Pharmacogenetics seems particularly important in diseases with a poor prognosis and treatments with potentially serious side effects. Pharmacogenetics testing is reimbursed in the case of serious side effects or unexpected ineffectiveness. 95% of patients in the Netherlands have at least one abnormality in the panel of genes for which guidance is available. The KNMP (Royal Dutch Pharmacists' Association) provides dosing advice based on genotype for 80 medicines, 27 of which are regularly prescribed in primary health care.

Clinical Application of Pharmacogenetics: Where are We Now?

PubMed Central

2014-01-01

Pharmacogenetic (PGx) testing has the potential to improve drug therapy in an individual by informing appropriate drug dosing or drug selection in order to maximize efficacy and safety. Although multiple studies have illustrated the potential benefits of such testing when applied to specific drugs across a broad range of therapy areas, the uptake of PGx testing in routine clinical practice has been relatively limited. Implementation appears to be hampered by the absence of sufficiently strong evidence linking the results of testing with actionable benefits in terms of clinical outcomes. Meanwhile, there are now adequate data to allow dosing recommendations as have been developed by bodies including the Dutch Pharmacogenetics Working Group (DPWG) and the Clinical Pharmacogenetics Implementation Consortium (CPIC) in several settings, including TPMT/thiopurines, CYP2C19/clopidogrel, CYP2D6/codeine, VKORC1-CYP2C9/warfarin, HLA-B*5701/abacavir, SLCO1B1/simvastatin and HLAB*5801/allopurinol. The International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) and the International Association of Therapeutic Drug Monitoring and Clinical Toxicology (IATDMCT) have also recently initiated surveys in order to better understand the extent of, and the role played by, PGx testing in clinical practice. This should help identify where further training and education may be beneficial. To this end, in collaboration with ESPT, the IFCC Pharmacogenetic Laboratory Network has now been formed, with the aim of improving the uptake and quality of PGx testing. PMID:27683445

Pharmacogenetics in the Brazilian Population

PubMed Central

Suarez-Kurtz, Guilherme

2010-01-01

Brazil is the fifth largest country in the world and its present population, in excess of 190;million, is highly heterogeneous, as a result of centuries of admixture between Amerindians, Europeans, and Sub-Saharan Africans. The estimated individual proportions of biogeographical ancestry vary widely and continuously among Brazilians: most individuals, irrespective of self-identification as White, Brown or Black – the major categories of the Brazilian Census “race/color” system – have significant degrees of European and African ancestry, while a sizeable number display also Amerindian ancestry. These features have important pharmacogenetic (PGx) implications: first, extrapolation of PGx data from relatively well-defined ethnic groups is clearly not applicable to the majority of Brazilians; second, the frequency distribution of polymorphisms in pharmacogenes (e.g., CYP3A5, CYP2C9, GSTM1, ABCB1, GSTM3, VKORC, etc) varies continuously among Brazilians and is not captured by race/color self-identification; third, the intrinsic heterogeneity of the Brazilian population must be acknowledged in the design and interpretation of PGx studies in order to avoid spurious conclusions based on improper matching of study cohorts. The peculiarities of PGx in Brazilians are illustrated with data for different therapeutic groups, such as anticoagulants, HIV protease inhibitors and non-steroidal antinflammatory drugs, and the challenges and advantages created by population admixture for the study and implementation of PGx are discussed. PGx data for Amerindian groups and Brazilian-born, first-generation Japanese are presented to illustrate the rich diversity of the Brazilian population. Finally, I introduce the reader to the Brazilian Pharmacogenetic Network or Refargen1, a nation-wide consortium of research groups, with the mission to provide leadership in PGx research and education in Brazil, with a population health impact. PMID:21833165

[Pharmacogenetics and the treatment of addiction].

PubMed

Schellekens, Arnt

2013-01-01

This article describes the current scientific knowledge regarding pharmacogenetic predictors of treatment outcome for substance-dependent patients. PubMed was searched for articles on pharmacogenetics and addiction. This search yielded 53 articles, of which 27 were selected. The most promising pharmacogenetic findings are related to the treatment of alcohol dependence. Genetic variation in the µ-opioid receptor (OPRM1) and the serotonin transporter (5-HTTLPR) appear to be associated with treatment outcomes for naltrexone and ondansetron, respectively. Genetic variation in CYP2D6 is related to efficacy of methadone treatment for opiate dependence. Pharmacogenetics may help explain the great inter-individual variation in treatment response. In the future, treatment matching, based on genetic characteristics of individual patients, could lead to a 'personalized medicine' approach. Pharmacogenetic matching of naltrexone in alcohol-dependent carriers of the OPRM1 G-allele currently seems most promising.

Development of a Post-Graduate Year 2 Pharmacy Residency in Clinical Pharmacogenetics

PubMed Central

Hoffman, James M.; Gammal, Roseann S.; Relling, Mary V.; Crews, Kristine R.

2017-01-01

Purpose The structure and development of an innovative clinical pharmacogenetics post-graduate year 2 (PGY2) ASHP-accredited residency program is described. Summary The advent of the era of genomics has left practitioners wondering how to interpret the data obtained from sequencing and genotyping patients. In order to train the next leaders in the area of implementing pharmacogenetics, St. Jude Children’s Research Hospital established the first accredited residency program in clinical pharmacogenetics. The 12-month long PGY2 residency was created in accordance with the ASHP standards for advanced practice residencies. The resident learns to optimize patient outcomes through the expert provision of evidence-based, patient-centered precision medicine as an integral part of an interdisciplinary team. The resident gains hands-on experience in a dynamic environment regarding all aspects of running a clinical pharmacogenetics service. Since the first resident graduated in 2012, the program has graduated one resident each year. Conclusion To fill a need for pharmacists trained in pharmacogenetics, an innovative PGY2 residency in clinical pharmacogenetics was successfully developed. Upon completion of the program, residents are equipped with the clinical skills and necessary experience to drive precision medicine forward and lead the implementation of pharmacogenetics in various healthcare settings. PMID:28274984

Key observations from the NHLBI Asthma Clinical Research Network.

PubMed

Szefler, Stanley J; Chinchilli, Vernon M; Israel, Elliot; Denlinger, Loren Clark; Lemanske, Robert F; Calhoun, William; Peters, Stephen P

2012-05-01

The National Heart, Lung and Blood Institute (NHLBI) Asthma Clinical Research Network (ACRN) recently completed its work after 20 years of collaboration as a multicentre clinical trial network. When formed, its stated mission was to perform multiple controlled clinical trials for treating patients with asthma by dispassionately examining new and existing therapies, and to rapidly communicate its findings to the medical community. The ACRN conducted 15 major clinical trials. In addition, clinical data, manual of operations, protocols and template informed consents from all ACRN trials are available via NHLBI BioLINCC (https://biolincc.nhlbi.nih.gov/studies/). This network contributed major insights into the use of inhaled corticosteroids, short-acting and long-acting ß-adrenergic agonists, leukotriene receptor antagonists, and novel agents (tiotropium, colchicine and macrolide antibiotics). They also pioneered studies of the variability in drug response, predictors of treatment response and pharmacogenetics. This review highlights the major research observations from the ACRN that have impacted the current management of asthma.

Pharmacogenetics.

PubMed

Roses, A D

2001-10-01

Pharmacogenetics is the variability of drug response due to inherited characteristics in individuals. Drug metabolizing enzymes have been studied for decades, first as chemical reactions and, more recently, as specific polymorphisms of known molecules. With the availability of whole-genome single-nucleotide polymorphism (SNP) maps, it will soon be possible to create an SNP profile for patients who experience adverse events (AEs) or who respond clinically to the medicine (efficacy). Proof-of-principle experiments have demonstrated that high density SNP maps in chromosomal regions of genetic linkage facilitate the identification of susceptibility disease genes. Whole-genome SNP mapping analyses aimed at determining linkage disequilibrium (LD) profiles along an ordered human genome backbone are in progress. SNP 'fingerprints' or SNP PRINTs(sm) will be used to identify patients at greater risk of an AE, or those patients with a greater chance of responding to a medicine. As LD maps for various ethnic populations are constructed, the number of SNPs necessary to measure for an individual will decrease. Standardized pharmacogenetic maps for drug registration and post-marketing surveillance will result in safer, more effective and more cost-efficient medicines. The timing of these pharmacogenetic applications will occur over the next 5 years. In contrast, the benefits of pharmacogenomic applications such as the identification of new tractable targets will not be visible as new medicines for 7-12 years, due to the lengthy drug development and registration processes.

Clinical application of pharmacogenetics: focusing on practical issues.

PubMed

Chang, Matthew T; McCarthy, Jeanette J; Shin, Jaekyu

2015-01-01

Recent large-scale genetic-based studies have transformed the field of pharmacogenetics to identify, characterize and leverage genetic information to inform patient care. Genetic testing can be used to alter drug selection, optimize drug dosing and prevent unnecessary adverse events. As precision medicine becomes the mainstay in the clinic, it becomes critical for clinicians to utilize pharmacogenetics to guide patient care. One primary challenge is identifying patients where genetic tests that can potentially impact patient care. To address this challenge, our review highlights many practical issues clinicians may encounter: identifying candidate patients and clinical laboratories for pharmacogenetic testing, selecting highly curated resources to help asses test validity, reimbursing costs of pharmacogenetic tests, and interpreting of pharmacogenetic test results.

Fundamentals of Pharmacogenetics in Personalized, Precision Medicine.

PubMed

Valdes, Roland; Yin, DeLu Tyler

2016-09-01

This article introduces fundamental principles of pharmacogenetics as applied to personalized and precision medicine. Pharmacogenetics establishes relationships between pharmacology and genetics by connecting phenotypes and genotypes in predicting the response of therapeutics in individual patients. We describe differences between precision and personalized medicine and relate principles of pharmacokinetics and pharmacodynamics to applications in laboratory medicine. We also review basic principles of pharmacogenetics, including its evolution, how it enables the practice of personalized therapeutics, and the role of the clinical laboratory. These fundamentals are a segue for understanding specific clinical applications of pharmacogenetics described in subsequent articles in this issue. Copyright © 2016 Elsevier Inc. All rights reserved.

Pharmacogenetics and the print media: what is the public told?

PubMed

Almomani, Basima; Hawwa, Ahmed F; Goodfellow, Nicola A; Millership, Jeffrey S; McElnay, James C

2015-05-09

Pharmacogenetics is a rapidly growing field that aims to identify the genes that influence drug response. This science can be used as a powerful tool to tailor drug treatment to the genetic makeup of individuals. The present study explores the coverage of the topic of pharmacogenetics and its potential benefit in personalised medicine by the UK newsprint media. The LexisNexis database was used to identify and retrieve full text articles from the 10 highest circulation national daily newspapers and their Sunday equivalents in the UK. Content analysis of newspaper articles which referenced pharmacogenetic testing was carried out. A second researcher coded a random sample (21%) of newspaper articles to establish the inter-rater reliability of coding. Of the 256 articles captured by the search terms, 96 articles (with pharmacogenetics as a major component) met the study inclusion criteria. The majority of articles over-stated the benefits of pharmacogenetic testing while paying less attention to the associated risks. Overall beneficial effects were mentioned 5.3 times more frequently than risks (p < 0.001). The most common illnesses for which pharmacogenetically based personalised medicine was discussed were cancer, cardiovascular disease and CNS diseases. Only 13% of newspaper articles that cited a specific scientific study mentioned this link in the article. There was a positive correlation between the size of the article and both the number of benefits and risks stated (P < 0.01). More comprehensive coverage of the area of personalised medicine within the print media is needed to inform public debate on the inclusion of pharmacogentic testing in routine practice.

Pharmacogenetics of Vascular Risk Factors in Alzheimer's Disease.

PubMed

Cacabelos, Ramón; Meyyazhagan, Arun; Carril, Juan C; Cacabelos, Pablo; Teijido, Óscar

2018-01-03

Alzheimer's disease (AD) is a polygenic/complex disorder in which genomic, epigenomic, cerebrovascular, metabolic, and environmental factors converge to define a progressive neurodegenerative phenotype. Pharmacogenetics is a major determinant of therapeutic outcome in AD. Different categories of genes are potentially involved in the pharmacogenetic network responsible for drug efficacy and safety, including pathogenic, mechanistic, metabolic, transporter, and pleiotropic genes. However, most drugs exert pleiotropic effects that are promiscuously regulated for different gene products. Only 20% of the Caucasian population are extensive metabolizers for tetragenic haplotypes integrating CYP2D6-CYP2C19-CYP2C9-CYP3A4/5 variants. Patients harboring CYP-related poor (PM) and/or ultra-rapid (UM) geno-phenotypes display more irregular profiles in drug metabolism than extensive (EM) or intermediate (IM) metabolizers. Among 111 pentagenic ( APOE-APOB-APOC3-CETP-LPL ) haplotypes associated with lipid metabolism, carriers of the H26 haplotype (23-TT-CG-AG-CC) exhibit the lowest cholesterol levels, and patients with the H104 haplotype (44-CC-CC-AA-CC) are severely hypercholesterolemic. Furthermore, APOE , NOS3 , ACE , AGT , and CYP variants influence the therapeutic response to hypotensive drugs in AD patients with hypertension. Consequently, the implementation of pharmacogenetic procedures may optimize therapeutics in AD patients under polypharmacy regimes for the treatment of concomitant vascular disorders.

Clinical and regulatory considerations in pharmacogenetic testing.

PubMed

Schuck, Robert N; Marek, Elizabeth; Rogers, Hobart; Pacanowski, Michael

2016-12-01

Both regulatory science and clinical practice rely on best available scientific data to guide decision-making. However, changes in clinical practice may be driven by numerous other factors such as cost. In this review, we reexamine noteworthy examples where pharmacogenetic testing information was added to drug labeling to explore how the available evidence, potential public health impact, and predictive utility of each pharmacogenetic biomarker impacts clinical uptake. Advances in the field of pharmacogenetics have led to new discoveries about the genetic basis for variability in drug response. The Food and Drug Administration recognizes the value of pharmacogenetic testing strategies and has been proactive about incorporating pharmacogenetic information into the labeling of both new drugs and drugs already on the market. Although some examples have readily translated to routine clinical practice, clinical uptake of genetic testing for many drugs has been limited. Both regulatory science and clinical practice rely on data-driven approaches to guide decision making; however, additional factors are also important in clinical practice that do not impact regulatory decision making, and these considerations may result in heterogeneity in clinical uptake of pharmacogenetic testing. Copyright © 2016 by the American Society of Health-System Pharmacists, Inc. All rights reserved.

P450 Pharmacogenetics in Indigenous North American Populations

PubMed Central

Claw, Katrina G.; Robinson, Renee F.; Boyer, Bert B.; Burke, Wylie; Thummel, Kenneth E.

2018-01-01

Indigenous North American populations, including American Indian and Alaska Native peoples in the United States, the First Nations, Métis and Inuit peoples in Canada and Amerindians in Mexico, are historically under-represented in biomedical research, including genomic research on drug disposition and response. Without adequate representation in pharmacogenetic studies establishing genotype-phenotype relationships, Indigenous populations may not benefit fully from new innovations in precision medicine testing to tailor and improve the safety and efficacy of drug treatment, resulting in health care disparities. The purpose of this review is to summarize and evaluate what is currently known about cytochrome P450 genetic variation in Indigenous populations in North America and to highlight the importance of including these groups in future pharmacogenetic studies for implementation of personalized drug therapy. PMID:29389890

Implementation of inpatient models of pharmacogenetics programs

PubMed Central

Cavallari, Larisa H.; Lee, Craig R.; Duarte, Julio D.; Nutescu, Edith A.; Weitzel, Kristin W.; Stouffer, George A.; Johnson, Julie A.

2017-01-01

Purpose The operational elements essential for establishing an inpatient pharmacogenetic service are reviewed, and the role of the pharmacist in the provision of genotype-guided drug therapy in pharmacogenetics programs at three institutions is highlighted. Summary Pharmacists are well positioned to assume important roles in facilitating the clinical use of genetic information to optimize drug therapy given their expertise in clinical pharmacology and therapeutics. Pharmacists have assumed important roles in implementing inpatient pharmacogenetics programs. This includes programs designed to incorporate genetic test results to optimize antiplatelet drug selection after percutaneous coronary intervention and personalize warfarin dosing. Pharmacist involvement occurs on many levels, including championing and leading pharmacogenetics implementation efforts, establishing clinical processes to support genotype-guided therapy, assisting the clinical staff with interpreting genetic test results and applying them to prescribing decisions, and educating other healthcare providers and patients on genomic medicine. The three inpatient pharmacogenetics programs described use reactive versus preemptive genotyping, the most feasible approach under the current third-party payment structure. All three sites also follow Clinical Pharmacogenetics Implementation Consortium guidelines for drug therapy recommendations based on genetic test results. Conclusion With the clinical emergence of pharmacogenetics into the inpatient setting, it is important that pharmacists caring for hospitalized patients are well prepared to serve as experts in interpreting and applying genetic test results to guide drug therapy decisions. Since genetic test results may not be available until after patient discharge, pharmacists practicing in the ambulatory care setting should also be prepared to assist with genotype-guided drug therapy as part of transitions in care. PMID:27864202

Progress and Promise of Attention-Deficit Hyperactivity Disorder Pharmacogenetics

PubMed Central

Froehlich, Tanya E.; McGough, James J.; Stein, Mark A.

2010-01-01

One strategy for understanding variability in attention-deficit hyperactivity disorder (ADHD) medication response, and therefore redressing the current trial-and-error approach to ADHD medication management, is to identify genetic moderators of treatment. This article summarizes ADHD pharmacogenetic investigative efforts to date, which have primarily focused on short-term response to methylphenidate and largely been limited by modest sample sizes. The most well studied genes include the dopamine transporter and dopamine D4 receptor, with additional genes that have been significantly associated with stimulant medication response including the adrenergic α2A-receptor, catechol-O-methyltransferase, D5 receptor, noradrenaline (norepinephrine) transporter protein 1 and synaptosomal-associated protein 25 kDa. Unfortunately, results of current ADHD pharmacogenetic studies have not been entirely consistent, possibly due to differences in study design, medication dosing regimens and outcome measures. Future directions for ADHD pharmacogenetics investigations may include examination of drug-metabolizing enzymes and a wider range of stimulant and non-stimulant medications. In addition, researchers are increasingly interested in going beyond the individual candidate gene approach to investigate gene-gene interactions or pathways, effect modification by additional environmental exposures and whole genome approaches. Advancements in ADHD pharmacogenetics will be facilitated by multi-site collaborations to obtain larger sample sizes using standardized protocols. Although ADHD pharmacogenetic efforts are still in a relatively early stage, their potential clinical applications may include the development of treatment efficacy and adverse effect prediction algorithms that incorporate the interplay of genetic and environmental factors, as well as the development of novel ADHD treatments. PMID:20088618

Evidence and resources to implement Pharmacogenetic Knowledge for Precision Medicine

PubMed Central

Caudle, Kelly E.; Gammal, Roseann S.; Whirl-Carrillo, Michelle; Hoffman, James M.; Relling, Mary V.; Klein, Teri E.

2016-01-01

Purpose Implementation of pharmacogenetics into clinical practice has been relatively slow despite substantial scientific progress over the last decade. One barrier that inhibits uptake of pharmacogenetics into routine clinical practice is the lack of knowledge of how to translate a genetic test into a clinical action based on current evidence. The purpose of this paper is to describe the current state of pharmacogenetic evidence and evidence-based resources that facilitate the uptake of pharmacogenetics into clinical practice. Summary Controversy exists over the required evidence threshold needed for routine clinical implementation of pharmacogenetics. Large randomized controlled trials are not clinically feasible or necessary for many pharmacogenetic applications. Online resources exist like the Clinical Pharmacogenetics Implementation Consortium (CPIC) and the Pharmacogenomics Knowledgebase (PharmGKB) that provide freely available, evidence-based resources that facilitate the translation of genetic laboratory test results into actionable prescribing recommendations for specific drugs. Conclusion Resources provided by organizations such as CPIC and PharmGKB that use standardized approaches to evaluate the literature and provide clinical guidance are essential for the implementation of pharmacogenetics into routine clinical practice. PMID:27864205

Implementation of inpatient models of pharmacogenetics programs.

PubMed

Cavallari, Larisa H; Lee, Craig R; Duarte, Julio D; Nutescu, Edith A; Weitzel, Kristin W; Stouffer, George A; Johnson, Julie A

2016-12-01

The operational elements essential for establishing an inpatient pharmacogenetic service are reviewed, and the role of the pharmacist in the provision of genotype-guided drug therapy in pharmacogenetics programs at three institutions is highlighted. Pharmacists are well positioned to assume important roles in facilitating the clinical use of genetic information to optimize drug therapy given their expertise in clinical pharmacology and therapeutics. Pharmacists have assumed important roles in implementing inpatient pharmacogenetics programs. This includes programs designed to incorporate genetic test results to optimize antiplatelet drug selection after percutaneous coronary intervention and personalize warfarin dosing. Pharmacist involvement occurs on many levels, including championing and leading pharmacogenetics implementation efforts, establishing clinical processes to support genotype-guided therapy, assisting the clinical staff with interpreting genetic test results and applying them to prescribing decisions, and educating other healthcare providers and patients on genomic medicine. The three inpatient pharmacogenetics programs described use reactive versus preemptive genotyping, the most feasible approach under the current third-party payment structure. All three sites also follow Clinical Pharmacogenetics Implementation Consortium guidelines for drug therapy recommendations based on genetic test results. With the clinical emergence of pharmacogenetics into the inpatient setting, it is important that pharmacists caring for hospitalized patients are well prepared to serve as experts in interpreting and applying genetic test results to guide drug therapy decisions. Since genetic test results may not be available until after patient discharge, pharmacists practicing in the ambulatory care setting should also be prepared to assist with genotype-guided drug therapy as part of transitions in care. Copyright © 2016 by the American Society of Health

Personalized medicine: is it a pharmacogenetic mirage?

PubMed Central

Shah, Rashmi R; Shah, Devron R

2012-01-01

The notion of personalized medicine has developed from the application of the discipline of pharmacogenetics to clinical medicine. Although the clinical relevance of genetically-determined inter-individual differences in pharmacokinetics is poorly understood, and the genotype-phenotype association data on clinical outcomes often inconsistent, officially approved drug labels frequently include pharmacogenetic information concerning the safety and/or efficacy of a number of drugs and refer to the availability of the pharmacogenetic test concerned. Regulatory authorities differ in their approach to these issues. Evidence emerging subsequently has generally revealed the pharmacogenetic information included in the label to be premature. Revised drugs labels, together with a flurry of other collateral activities, have raised public expectations of personalized medicine, promoted as ‘the right drug at the right dose the first time.’ These expectations place the prescribing physician in a dilemma and at risk of litigation, especially when evidence-based information on genotype-related dosing schedules is to all intent and purposes non-existent and guidelines, intended to improve the clinical utility of available pharmacogenetic information or tests, distance themselves from any responsibility. Lack of efficacy or an adverse drug reaction is frequently related to non-genetic factors. Phenoconversion, arising from drug interactions, poses another often neglected challenge to any potential success of personalized medicine by mimicking genetically-determined enzyme deficiency. A more realistic promotion of personalized medicine should acknowledge current limitations and emphasize that pharmacogenetic testing can only improve the likelihood of diminishing a specific toxic effect or increasing the likelihood of a beneficial effect and that application of pharmacogenetics to clinical medicine cannot adequately predict drug response in individual patients. PMID:22591598

Pharmacogenetics of β-Blockers

PubMed Central

Shin, Jaekyu; Johnson, Julie A.

2009-01-01

β-Blockers are an important cardiovascular drug class, recommended as first-line treatment of numerous diseases such as heart failure, hypertension, and angina, as well as treatment after myocardial infarction. However, responses to a β-blocker are variable among patients. Results of numerous studies now suggest that genetic polymorphisms may contribute to variability in responses to β-blockers. This review summarizes the pharmacogenetic data for β-blockers in patients with various diseases and discusses the potential implications of β-blocker pharmacogenetics in clinical practice. PMID:17542770

Pharmacogenetics and personalised medicine: maintain a critical approach.

PubMed

2013-06-01

The purpose of pharmacogenetics is to offer"personalised" treatment, in which a drug is only prescribed to patients in whom it is very likely to be effective, or to withhold a drug from patients at increased risk of adverse effects. Pharmacogenetics requires the use of genetic tests which, as with any other diagnostic test, must be evaluated for their discriminatory power (sensitivity, specificity, etc.). These evaluations are sometimes biased. Pharmacogenetics has been heralded as a means of tailoring cancer therapy. However large clinical trials with demanding clinical endpoints are often disappointing, despite initially encouraging results. Pharmacogenetic information is included in many summaries of product characteristics for non-cancer drugs, mainly in order to reduce the frequency of certain serious adverse effects. In summary, pharmacogenetics theoretically represents a step forward but must be evaluated in rigorous clinical trials, as is the case with all other "therapeutic tools".

Pharmacology and pharmacogenetics of pediatric ADHD with associated aggression: a review.

PubMed

Patel, Bianca D; Barzman, Drew H

2013-12-01

Attention deficit hyperactivity disorder (ADHD) is often associated with symptoms of aggression in children and adolescents. Clinically, this is complex because aggression can be from hyperactivity and impulsivity, or could be a distinct symptom from a comorbid diagnosis. Past research has recommended first treating the primary disorder of ADHD. Stimulants are the most common treatment for pediatric ADHD, which can be helpful in decreasing aggressive behaviors. Alpha-adrenergic agonists and atomoxetine (ATX) are non-stimulant medications for ADHD and aggression, but more research is necessary to compare these drugs to stimulants. If aggressive symptoms do not improve from treating the primary disorder, aggression can be treated separately. Risperidone, lithium, valproic acid, clonidine, and guanfacine have shown positive results in reducing aggression, but studies including children with aggression and ADHD are limited. The variability in treatment tolerability in patients has stimulated research in pharmacogenetics for ADHD. Although this field is still emerging, research has found evidence supporting a link between the response rate of methylphenidate and the dopamine transporter (DAT1) and a link between the metabolism rate of atomoxetine and hepatic cytochrome 450 isozymes. Pharmacogenetics may be relevant to ADHD and associated aggression. Further research in pharmacogenetics will strive to identify patterns of genetic variations that can tailor individual treatments.

Pharmacogenetics of Vascular Risk Factors in Alzheimer’s Disease

PubMed Central

Cacabelos, Ramón; Meyyazhagan, Arun; Carril, Juan C.; Cacabelos, Pablo; Teijido, Óscar

2018-01-01

Alzheimer’s disease (AD) is a polygenic/complex disorder in which genomic, epigenomic, cerebrovascular, metabolic, and environmental factors converge to define a progressive neurodegenerative phenotype. Pharmacogenetics is a major determinant of therapeutic outcome in AD. Different categories of genes are potentially involved in the pharmacogenetic network responsible for drug efficacy and safety, including pathogenic, mechanistic, metabolic, transporter, and pleiotropic genes. However, most drugs exert pleiotropic effects that are promiscuously regulated for different gene products. Only 20% of the Caucasian population are extensive metabolizers for tetragenic haplotypes integrating CYP2D6-CYP2C19-CYP2C9-CYP3A4/5 variants. Patients harboring CYP-related poor (PM) and/or ultra-rapid (UM) geno-phenotypes display more irregular profiles in drug metabolism than extensive (EM) or intermediate (IM) metabolizers. Among 111 pentagenic (APOE-APOB-APOC3-CETP-LPL) haplotypes associated with lipid metabolism, carriers of the H26 haplotype (23-TT-CG-AG-CC) exhibit the lowest cholesterol levels, and patients with the H104 haplotype (44-CC-CC-AA-CC) are severely hypercholesterolemic. Furthermore, APOE, NOS3, ACE, AGT, and CYP variants influence the therapeutic response to hypotensive drugs in AD patients with hypertension. Consequently, the implementation of pharmacogenetic procedures may optimize therapeutics in AD patients under polypharmacy regimes for the treatment of concomitant vascular disorders. PMID:29301387

Pharmacogenetics in dermatology: a patient-centered update.

PubMed

Comfere, Nneka I; Ikediobi, Ogechi N; Peters, Margot S; el-Azhary, Rokea A; Gibson, Lawrence E

2013-08-01

The term pharmacogenetics is used to describe an evolving field that aims to understand the relationship between individual variations in genetic sequence and differences in the therapeutic and toxic response to medications. The promise of pharmacogenetics is empowerment of clinicians with information that will enable them to personalize drug therapy - to prescribe the right medication at the right dose for each patient, while minimizing adverse effects. Despite dramatic advances, wide application of pharmacogenetics to clinical practice has been slow for a number of reasons, including lack of evidence-based therapeutic guidelines as well as ethical concerns and cost. To illustrate applications to dermatology practice, we present three clinical scenarios that serve as a springboard for discussion of the principles of pharmacogenetics and how they can be used to guide treatment with azathioprine, 5-fluorouracil, and trastuzumab. The therapeutic and toxic effects of a given medication ultimately depend on its combined pharmacokinetic, pharmacodynamic, and pharmacogenetic properties in a given individual. Pharmacodynamic properties of individual medications must be correlated with single nucleotide polymorphisms. Test recommendations and standardization of therapy for specific disorders can then be established. © 2013 The International Society of Dermatology.

Pharmacogenetics and outcome with antipsychotic drugs.

PubMed

Pouget, Jennie G; Shams, Tahireh A; Tiwari, Arun K; Müller, Daniel J

2014-12-01

Antipsychotic medications are the gold-standard treatment for schizophrenia, and are often prescribed for other mental conditions. However, the efficacy and side-effect profiles of these drugs are heterogeneous, with large interindividual variability. As a result, treatment selection remains a largely trial-and-error process, with many failed treatment regimens endured before finding a tolerable balance between symptom management and side effects. Much of the interindividual variability in response and side effects is due to genetic factors (heritability, h(2)~ 0.60-0.80). Pharmacogenetics is an emerging field that holds the potential to facilitate the selection of the best medication for a particular patient, based on his or her genetic information. In this review we discuss the most promising genetic markers of antipsychotic treatment outcomes, and present current translational research efforts that aim to bring these pharmacogenetic findings to the clinic in the near future.

Pharmacogenetics and outcome with antipsychotic drugs

PubMed Central

Pouget, Jennie G.; Shams, Tahireh A.; Tiwari, Arun K.; Müller, Daniel J.

2014-01-01

Antipsychotic medications are the gold-standard treatment for schizophrenia, and are often prescribed for other mental conditions. However, the efficacy and side-effect profiles of these drugs are heterogeneous, with large interindividual variability. As a result, treatment selection remains a largely trial-and-error process, with many failed treatment regimens endured before finding a tolerable balance between symptom management and side effects. Much of the interindividual variability in response and side effects is due to genetic factors (heritability, h2~ 0.60-0.80). Pharmacogenetics is an emerging field that holds the potential to facilitate the selection of the best medication for a particular patient, based on his or her genetic information. In this review we discuss the most promising genetic markers of antipsychotic treatment outcomes, and present current translational research efforts that aim to bring these pharmacogenetic findings to the clinic in the near future. PMID:25733959

Positive perception of pharmacogenetic testing for psychotropic medications

PubMed Central

Lanktree, Matthew B; Zai, Gwyneth; VanderBeek, Laura E; Giuffra, Daniel E; Smithson, David S; Kipp, Lucas B; Dalseg, Timothy R; Speechley, Mark; Kennedy, James L

2014-01-01

Introduction Pharmacogenetics attempts to identify inter-individual genetic differences that are predictive of variable drug response and propensity to side effects, with the prospect of assisting physicians to select the most appropriate drug and dosage for treatment. However, many concerns regarding genetic tests exist. We sought to test the opinions of undergraduate science and medical students in southern Ontario universities toward pharmacogenetic testing. Methods and Results Questionnaires were completed by 910 undergraduate medicine and science students from 2005 to 2007. Despite students' concerns that the results of genetic tests may be used for other purposes without consent (71%) or lead to discrimination (78%), an overwhelming number of students were in favor of pharmacogenetic testing (90%). Discussion To our knowledge, this study is the first to survey a large sample for their attitude toward pharmacogenetic testing for psychotropic medications. Our results indicate that, although concerns remain and scientific advancements are required, respondents were in support of pharmacogenetic testing for medications used to treat schizophrenia. © 2014 The Authors. Human Psychopharmacology: Clinical and Experimental published by John Wiley & Sons, Ltd. PMID:24604560

Pharmacogenetics and pharmacogenomics as tools in cancer therapy.

PubMed

Rodríguez-Vicente, Ana E; Lumbreras, Eva; Hernández, Jesus M; Martín, Miguel; Calles, Antonio; Otín, Carlos López; Algarra, Salvador Martín; Páez, David; Taron, Miquel

2016-03-01

Pharmacogenetics and pharmacogenomics (PGx) are rapidly growing fields that aim to elucidate the genetic basis for the interindividual differences in drug response. PGx approaches have been applied to many anticancer drugs in an effort to identify relevant inherited or acquired genetic variations that may predict patient response to chemotherapy and targeted therapies. In this article, we discuss the advances in the field of cancer pharmacogenetics and pharmacogenomics, driven by the recent technological advances and new revolutionary massive sequencing technologies and their application to elucidate the genetic bases for interindividual drug response and the development of biomarkers able to personalize drug treatments. Specifically, we present recent progress in breast cancer molecular classifiers, cell-free circulating DNA as a prognostic and predictive biomarker in cancer, patient-derived tumor xenograft models, chronic lymphocytic leukemia genomic landscape, and current pharmacogenetic advances in colorectal cancer. This review is based on the lectures presented by the speakers of the symposium "Pharmacogenetics and Pharmacogenomics as Tools in Cancer Therapy" from the VII Conference of the Spanish Pharmacogenetics and Pharmacogenomics Society (SEFF), held in Madrid (Spain) on April 21, 2015.

Pharmacogenetics predictive of response and toxicity in acute lymphoblastic leukemia therapy.

PubMed

Mei, Lin; Ontiveros, Evelena P; Griffiths, Elizabeth A; Thompson, James E; Wang, Eunice S; Wetzler, Meir

2015-07-01

Acute lymphoblastic leukemia (ALL) is a relatively rare disease in adults accounting for no more than 20% of all cases of acute leukemia. By contrast with the pediatric population, in whom significant improvements in long term survival and even cure have been achieved over the last 30years, adult ALL remains a significant challenge. Overall survival in this group remains a relatively poor 20-40%. Modern research has focused on improved pharmacokinetics, novel pharmacogenetics and personalized principles to optimize the efficacy of the treatment while reducing toxicity. Here we review the pharmacogenetics of medications used in the management of patients with ALL, including l-asparaginase, glucocorticoids, 6-mercaptopurine, methotrexate, vincristine and tyrosine kinase inhibitors. Incorporating recent pharmacogenetic data, mainly from pediatric ALL, will provide novel perspective of predicting response and toxicity in both pediatric and adult ALL therapies. Copyright © 2015 Elsevier Ltd. All rights reserved.

Pharmacogenetics of schizophrenia.

PubMed

Reynolds, Gavin P; Templeman, Lucy A; Godlewska, Beata R

2006-08-01

There is substantial unexplained interindividual variability in the drug treatment of schizophrenia. A substantial proportion of patients respond inadequately to antipsychotic drugs, and many experience limiting side effects. As genetic factors are likely to contribute to this variability, the pharmacogenetics of schizophrenia has attracted substantial effort. The approaches have mainly been limited to association studies of polymorphisms in candidate genes, which have been indicated by the pharmacology of antipsychotic drugs. Although some advances have been made, particularly in understanding the pharmacogenetics of some limiting side effects, genetic prediction of symptom response remains elusive. Nevertheless, with improvements in defining the response phenotype in carefully assessed and homogeneous subject groups, the near future is likely to see the identification of genetic predictors of outcome that may inform the choice of pharmacotherapy.

Progress and prospects in pharmacogenetics of antidepressant drugs.

PubMed

Fabbri, Chiara; Crisafulli, Concetta; Calabrò, Marco; Spina, Edoardo; Serretti, Alessandro

2016-10-01

Depression is responsible for the most part of the personal and socio-economic burden due to psychiatric disorders. Since antidepressant response clusters in families, pharmacogenetics represents a meaningful tool to provide tailored treatments and improve the prognosis of depression. This review aims to summarize and discuss the pharmacogenetics of antidepressant drugs in major depressive disorder, with a focus on the most replicated genes, genome-wide association studies (GWAS), but also on the findings provided by new and promising analysis methods. In particular, multimarker tests such as pathway analysis and polygenic risk scores increase the power of detecting associations compared to the analysis of individual polymorphisms. Since genetic variants are not necessarily associated with a change in protein level, gene expression studies may provide complementary information to genetic studies. Finally, the pharmacogenetic tests that have been investigated for clinical application are discussed. Despite the lack of widespread clinical applications, preliminary results suggest that pharmacogenetics may be useful to guide antidepressant treatment. The US Food and Drug Administration included pharmacogenetic indications in the labeling of several antidepressants. This represented an important official recognition of the clinical relevance of genetic polymorphisms in antidepressant treatment.

Pharmacogenetics of the β2-Adrenergic Receptor Gene

PubMed Central

Ortega, Victor E.; Hawkins, Gregory A.; Peters, Stephen P.; Bleecker, Eugene R.

2009-01-01

Asthma is a complex genetic disease with multiple genetic and environmental determinants contributing to the observed variability in response to common anti-asthma therapies. Asthma pharmacogenetic research has focused on multiple candidate genes including the β2-adrenergic receptor gene (ADRβ2) and its effect on individual responses to beta agonist therapy. At present, knowledge about the effects of ADRβ2 variation on therapeutic responses is evolving and should not alter current Asthma Guideline approaches consisting of the use of short acting beta agonists for as-needed symptom based therapy and the use of a regular long-acting beta agonist in combination with inhaled corticosteroid therapy for optimal control of asthma symptoms in those asthmatics who are not controlled on inhaled corticosteroid alone. This approach is based upon studies showing a consistent pharmacogenetic response to regular use of short acting beta agonists (SABA) and less consistent findings in studies evaluating long acting beta agonist (LABA). While emerging pharmacogenetic studies are provocative and should lead to functional approaches, conflicting data with responses to LABA therapy may be caused by factors that include small sample sizes of study populations and differences in experimental design that may limit the conclusions that may be drawn from these clinical trials at the present time. PMID:17996583

Pharmacogenetics in electroconvulsive therapy and adjunctive medications.

PubMed

Mirzakhani, Hooman; van Noorden, Martijn S; Swen, Jesse; Nozari, Ala; Guchelaar, Henk-Jan

2015-01-01

Electroconvulsive therapy (ECT) has shown apparent efficacy in treatment of patients with depression and other mental illnesses who do not respond to psychotropic medications or need urgent control of their symptoms. Pharmacogenetics contributes to an individual's sensitivity and response to a variety of drugs. Clinical insights into pharmacogenetics of ECT and adjunctive medications not only improves its safety and efficacy in the indicated patients, but can also lead to the identification of novel treatments in psychiatric disorders through understanding of potential molecular and biological mechanisms involved. In this review, we explore the indications of pharmacogenetics role in safety and efficacy of ECT and present the evidence for its role in patients with psychiatric disorders undergoing ECT.

Modern molecular study of weight gain related to antidepressant treatment: clinical implications of the pharmacogenetic testing.

PubMed

Ageu, Luminiţa Ştefania; Levai, Codrina Mihaela; Andreescu, Nicoleta Ioana; Grigoraş, Mirela Loredana; Hogea, Lavinia Maria; Chiriac, Daniela Veronica; Folescu, Roxana; Bredicean, Ana Cristina; Nussbaum, Liliana Maria; Enătescu, Virgil Radu; Poroch, Vladimir; Lupu, Viorel; Puiu, Maria; Nussbaum, Laura Alexandra

2018-01-01

Antidepressant medication influences cellular lipogenesis, being associated with metabolic side effects including weight gain. Due to the increasing use of antidepressants in children and adolescents, their metabolic and endocrine adverse effects are of particular concern, especially within this pediatric population that appears to be at greater risk. Genetic factors with a possible influence on antidepressant's adverse effects include CYP [cytochrome P450 (CYP450)] polymorphisms. We target to evaluate the efficacy of the pharmacogenetic testing, when prescribing antidepressants, in correlation with the occurrence of adverse events and weight gain. Our research was performed between the years 2010 and 2016, in the University Clinic of Child and Adolescent Psychiatry, Timisoara, Romania. We recruited 80 patients, children and adolescents with depressive disorders. Our study sample was divided in two groups: G1 - 40 patients took treatment after pharmacogenetic testing, and G2 - 40 patients without pharmacogenetic testing before the treatment election. Our results show statistically significant differences concerning the weight gain for groups G1 (with pharmacogenetic testing) and G2 (without pharmacogenetic testing). The CYP genotype and the pharmacogenetic testing, for choosing the personalized antidepressant therapy in children and adolescents with depressive disorders, proved to be good predictors for the response to antidepressants and the side effects registered, especially for weight gain. The significant correlations between the CYP polymorphisms for group G2 (without pharmacogenetic testing) and the weight gain/body mass index (BMI) increase, as major side effects induced by antidepressants, proved the fact that the pharmacogenetic screening is needed in the future clinical practice, allowing for individualized, tailored treatment, especially for at-risk pediatric categories.

Cholinesterase inhibitors in Alzheimer's disease and Lewy body spectrum disorders: the emerging pharmacogenetic story

PubMed Central

2009-01-01

This review provides an update on the current state of pharmacogenetic research in the treatment of Alzheimer's disease (AD) and Lewy body disease (LBD) as it pertains to the use of cholinesterase inhibitors (ChEI). AD and LBD are first reviewed from clinical and pathophysiological perspectives. This is followed by a discussion of ChEIs used in the symptomatic treatment of these conditions, focusing on their unique and overlapping pharmacokinetic and pharmacodynamic profiles, which can be used to identify candidate genes for pharmacogenetics studies. The literature published to date is then reviewed and limitations are discussed. This is followed by a discussion of potential endophenotypes which may help to refine future pharmacogenetic studies of response and adverse effects to ChEIs. PMID:20038497

Pharmacogenetic testing, informed consent and the problem of secondary information.

PubMed

Netzer, Christian; Biller-Andorno, Nikola

2004-08-01

Numerous benefits for patients have been predicted if prescribing decisions were routinely accompanied by pharmacogenetic testing. So far, little attention has been paid to the possibility that the routine application of this new technology could result in considerable harm to patients. This article emphasises that pharmacogenetic testing shares both the opportunities and the pitfalls with 'conventional' disease-genetic testing. It demonstrates that performing pharmacogenetic tests as well as interpreting the results are extraordinarily complex issues requiring a high level of expertise. It further argues that pharmacogenetic testing can have a huge impact on clinical decisions and may influence the therapeutic strategy as well as the clinical monitoring of a patient. This view challenges the predominant paradigm that pharmacogenetic testing will predict patients' responses to medicines, but that it will not provide any other significant disease-specific predictive information about the patient or family members. The article also questions published proposals to reduce the consent procedure for pharmacogenetic testing to a simple statement that the physician wishes to test a sample of the patient's DNA to see if a drug will be safe or whether it will work, and presents an alternative model that is better suited to protect patient's interests and to obtain meaningful informed consent. The paper concludes by outlining conditions for the application of pharmacogenetic testing in clinical practice in a way that can make full use of its potential benefits while minimising possible harm to patients and their families.

Pharmacogenetics of new analgesics

PubMed Central

Lötsch, Jörn; Geisslinger, Gerd

2011-01-01

Patient phenotypes in pharmacological pain treatment varies between individuals, which could be partly assigned to their genotypes regarding the targets of classical analgesics (OPRM1, PTGS2) or associated signalling pathways (KCNJ6). Translational and genetic research have identified new targets, for which new analgesics are being developed. This addresses voltage-gated sodium, calcium and potassium channels, for which SCN9A, CACNA1B, KCNQ2 and KCNQ3, respectively, are primary gene candidates because they code for the subunits of the respective channels targeted by analgesics currently in clinical development. Mutations in voltage gated transient receptor potential (TRPV) channels are known from genetic pain research and may modulate the effects of analgesics under development targeting TRPV1 or TRPV3. To this add ligand-gated ion channels including nicotinic acetylcholine receptors, ionotropic glutamate-gated receptors and ATP-gated purinergic P2X receptors with most important subunits coded by CHRNA4, GRIN2B and P2RX7. Among G protein coupled receptors, δ-opioid receptors (coded by OPRD1), cannabinoid receptors (CNR1 and CNR2), metabotropic glutamate receptors (mGluR5 coded by GRM5), bradykinin B1 (BDKRB1) and 5-HT1A (HTR1A) receptors are targeted by new analgesic substances. Finally, nerve growth factor (NGFB), its tyrosine kinase receptor (NTRK1) and the fatty acid amide hydrolase (FAAH) have become targets of interest. For most of these genes, functional variants have been associated with neuro-psychiatric disorders and not yet with analgesia. However, research on the genetic modulation of pain has already identified variants in these genes, relative to pain, which may facilitate the pharmacogenetic assessments of new analgesics. The increased number of candidate pharmacogenetic modulators of analgesic actions may open opportunities for the broader clinical implementation of genotyping information. PMID:20942817

The Pharmacist's Perspective on Pharmacogenetics Implementation.

PubMed

Weitendorf, Frederick; Reynolds, Kristen K

2016-09-01

The future for pharmacogenetics will continue to expand. Pharmacists can apply and incorporate drug knowledge in collaboration with other health providers using pharmacogenetics. Patients benefit with enhanced therapeutic outcomes that could lead to more streamlined drug approaches, fewer follow-up visits, cost savings, and shorter times to achieve therapeutic outcomes. As more drug-gene pathways are discovered and use of this knowledge increases, the potential for algorithm development for medication use will occur, resulting in better patient outcomes, higher standard of care, and reflect evidence-based medicine. Copyright © 2016 Elsevier Inc. All rights reserved.

β-Blocker pharmacogenetics in heart failure

PubMed Central

Shin, Jaekyu

2009-01-01

β-Blockers (metoprolol, bisoprolol, and carvedilol) are a cornerstone of heart failure (HF) treatment. However, it is well recognized that responses to a β-blocker are variable among patients with HF. Numerous studies now suggest that genetic polymorphisms may contribute to variability in responses to a β-blocker, including left ventricular ejection fraction improvement, survival, and hospitalization due to HF exacerbation. This review summarizes the pharmacogenetic data for β-blockers in patients with HF and discusses the potential implications of β-blocker pharmacogenetics for HF patients. PMID:18437562

Feasibility of implementing a comprehensive warfarin pharmacogenetics service.

PubMed

Nutescu, Edith A; Drozda, Katarzyna; Bress, Adam P; Galanter, William L; Stevenson, James; Stamos, Thomas D; Desai, Ankit A; Duarte, Julio D; Gordeuk, Victor; Peace, David; Kadkol, Shrihari S; Dodge, Carol; Saraf, Santosh; Garofalo, John; Krishnan, Jerry A; Garcia, Joe G N; Cavallari, Larisa H

2013-11-01

To determine the procedural feasibility of a pharmacist-led interdisciplinary service for providing genotype-guided warfarin dosing for hospitalized patients newly starting warfarin. Prospective observational study. A 438-bed tertiary care hospital affiliated with a large academic institution. Eighty patients who started warfarin therapy and were managed by a newly implemented pharmacogenetics service. All patients received routine warfarin genotyping and clinical pharmacogenetics consultation. The primary outcomes were percentage of genotype-guided dose recommendations available prior to the second warfarin dose and adherence of the medical staff to doses recommended by the pharmacogenetics service. Of 436 genotype orders placed during the first 6 months of the service, 190 (44%) were deemed appropriate. For the 80 patients on the service who consented to data collection, 76% of the genotypes were available prior to the second warfarin dose. The median (range) time from genotype order to genotype result was 26 hours (7-80 hrs), and the time to genotype-guided dose recommendation was 30 hours (7-80 hrs). A total of 73% of warfarin doses ordered by the medical staff were within 0.5 mg of the daily dose recommended by the pharmacogenetics consult service. Providing routine genotype-guided warfarin dosing supported by a pharmacogenetics consult service is feasible from a procedural standpoint, with most genotypes available prior to the second warfarin dose and good adherence to genotype-guided dose recommendations by the medical staff. © 2013 Pharmacotherapy Publications, Inc.

Feasibility of Implementing a Comprehensive Warfarin Pharmacogenetics Service

PubMed Central

Nutescu, Edith A.; Drozda, Katarzyna; Bress, Adam P.; Galanter, William L.; Stevenson, James; Stamos, Thomas D.; Desai, Ankit A.; Duarte, Julio D.; Gordeuk, Victor; Peace, David; Kadkol, ShriHari S.; Dodge, Carol; Saraf, Santosh; Garofalo, John; Krishnan, Jerry A.; Garcia, Joe G.N.; Cavallari, Larisa H.

2013-01-01

Objective To determine the procedural feasibility of a pharmacist-led interdisciplinary service for providing genotype-guided warfarin dosing for hospitalized patients newly starting warfarin. Design Prospective observational study Setting 483-bed hospital affiliated with a large academic institution Participants Eighty patients started on warfarin and managed by a newly implemented pharmacogenetics service. Intervention Routine warfarin genotyping and clinical pharmacogenetics consultation Measurements and Main Results The primary outcomes were percent of genotype-guided dose recommendations available prior to the second warfarin dose and adherence of the medical staff to doses recommended by the pharmacogenetics service. Of 436 genotype orders during the first 6 months of the service, 190 were deemed appropriate. For 80 patients on the service who consented to data collection, 77% of genotypes were available prior to the second warfarin dose. The median (range) time from the genotype order to the genotype result was 26 (7 to 80) hours, and the time to genotype-guided dosing recommendation was 30 (7 to 80) hours. Seventy-three percent of warfarin doses ordered by the medical staff were within 0.5 mg of the dose recommended by the pharmacogenetics consult service. Conclusions Providing routine genotype-guided warfarin dosing supported by a pharmacogenetics consult service is feasible from a procedural standpoint, with the majority of genotypes available prior to the second warfarin dose and good adherence to genotype-guided dose recommendations by the medical staff. PMID:23864527

Hot Topics in Pharmacogenetics of Age-Related Macular Degeneration.

PubMed

Schwartz, Stephen G; Brantley, Milam A; Kovach, Jaclyn L; Grzybowski, Andrzej

2017-01-01

Age-related macular degeneration (AMD) is a leading cause of irreversible visual loss and is primarily treated with nutritional supplementation as well as with anti-vascular endothelial growth factor (VEGF) agents for certain patients with neovascular disease. AMD is a complex disease with both genetic and environmental risk factors. In addition, treatment outcomes from nutritional supplementation and anti-VEGF agents vary considerably. Therefore, it is reasonable to suspect that there may be pharmacogenetic influences on these treatments. Many series have reported individual associations with variants in complement factor H (CFH), age-related maculopathy susceptibility 2 (ARMS2), and other loci. However, at this time there are no validated associations. With respect to AMD, pharmacogenetics remains an intriguing area of research but is not helpful for routine clinical management. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Pharmacogenetics in Neurodegenerative Diseases: Implications for Clinical Trials.

PubMed

Tortelli, Rosanna; Seripa, Davide; Panza, Francesco; Solfrizzi, Vincenzo; Logroscino, Giancarlo

2016-01-01

Pharmacogenetics has become extremely important over the last 20 years for identifying individuals more likely to be responsive to pharmacological interventions. The role of genetic background as a predictor of drug response is a young and mostly unexplored field in neurodegenerative diseases. Mendelian mutations in neurodegenerative diseases have been used as models for early diagnosis and intervention. On the other hand, genetic polymorphisms or risk factors for late-onset Alzheimer's disease (AD) or other neurodegenerative diseases, probably influencing drug response, are hardly taken into account in randomized clinical trial (RCT) design. The same is true for genetic variants in cytochrome P450 (CYP), the principal enzymes influencing drug metabolism. A better characterization of individual genetic background may optimize clinical trial design and personal drug response. This chapter describes the state of the art about the impact of genetic factors in RCTs on neurodegenerative disease, with AD, frontotemporal dementia, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease as examples. Furthermore, a brief description of the genetic bases of drug response focusing on neurodegenerative diseases will be conducted. The role of pharmacogenetics in RCTs for neurodegenerative diseases is still a young, unexplored, and promising field. Genetic tools allow increased sophistication in patient profiling and treatment optimization. Pharmaceutical companies are aware of the value of collecting genetic data during their RCTs. Pharmacogenetic research is bidirectional with RCTs: efficacy data are correlated with genetic polymorphisms, which in turn define subjects for treatment stratification. © 2016 S. Karger AG, Basel.

Pharmacogenetics of drug hypersensitivity

PubMed Central

Phillips, Elizabeth J; Mallal, Simon A

2010-01-01

Drug hypersensitivity reactions and severe cutaneous adverse drug reactions, such as Stevens–Johnson syndrome and toxic epidermal necrolysis, are examples of serious adverse drug reactions mediated through a combination of metabolic and immunological mechanisms that could traditionally not have been predicted based on the pharmacological characteristics of the drug alone. The discovery of new associations between these syndromes and specific HLA has created the promise that risk for these reactions could be predicted through pharmacogenetic screening, thereby avoiding serious morbidity and mortality associated with these types of drug reactions. Despite this, several hurdles exist in the translation of these associations into pharmacogenetic tests that could be routinely used in the clinical setting. HLA-B*5701 screening to prevent abacavir hypersensitivity syndrome is an example of a test now in widespread routine clinical use in the developed world. PMID:20602616

Knowledge of Pharmacogenetics among Healthcare Professionals and Faculty Members of Health Training Institutions in Ghana.

PubMed

Kudzi, W; Addy, B S; Dzudzor, B

2015-03-01

Pharmacogenetics has a potential for optimizing drug response and identifying risk of toxicity for patients. Pharmacogenetics knowledge of healthcare professionals and the unmet need for pharmacogenetics education in health training institutions are some of the challenges of integrating pharmacogenetics into routine medical practice. To assess pharmacogenetics knowledge among healthcare professionals and faculty members of health training institutions in Ghana. Semi-structured questionnaires were used to interview healthcare professionals from selected public and private hospitals. Faculty members from health training institutions were also interviewed. The respondents were Medical doctors 42 (46.7%), Pharmacists 29 (32.2%) and Nurses 19 (21.1%). Healthcare professionals rated their knowledge of Pharmacogenetics as Excellent 5 (5.6%), Very Good 10 (11.2%), Good 53 (60%) and Poor 19 (21.4%). Thirty-two faculty members from health training institutions were also interviewed. Faculty members rated their knowledge of pharmacogenetics as Excellent 2 (6.3%), Very Good 3 (9.4%), Good 9 (28.1%), Fair 12 (37.5%) and Poor 6 (18.8%). Thirty seven percent (12) of these faculty members said pharmacogenetics was not part of their institutions' curriculum, 7 (22%) did not know if pharmacogenetics was part of their curriculum and only 13 (40.6%) said it was part of their curriculum. Few healthcare professionals and faculty members of training institutions are aware of the discipline of pharmacogenetics. There is the need for continuous professional education on pharmacogenetics and development of competency standards for all healthcare professionals in Ghana.

Pharmacogenetics in cardiovascular diseases: State of the art and implementation-recommendations of the French National Network of Pharmacogenetics (RNPGx).

PubMed

Lamoureux, Fabien; Duflot, Thomas

2017-04-01

The use of genomic markers to predict drug response and effectiveness has the potential to improve healthcare by increasing drug efficacy and minimizing adverse effects. Polymorphisms associated with inter-individual variability in drug metabolism, transport, or pharmacodynamics of major cardiovascular drugs have been identified. These include single nucleotide polymorphisms (SNP) affecting clinical outcomes in patients receiving antiplatelet agents, oral anticoagulants and statins. Based on clinical evidence supporting genetic testing in the management of cardiovascular diseases using these drug classes, this short review presents clinical guidance regarding current pharmacogenetics implementation in routine medical practice. Copyright © 2017 Société française de pharmacologie et de thérapeutique. Published by Elsevier Masson SAS. All rights reserved.

Asthma pharmacogenetics and the development of genetic profiles for personalized medicine

PubMed Central

Ortega, Victor E; Meyers, Deborah A; Bleecker, Eugene R

2015-01-01

Human genetics research will be critical to the development of genetic profiles for personalized or precision medicine in asthma. Genetic profiles will consist of gene variants that predict individual disease susceptibility and risk for progression, predict which pharmacologic therapies will result in a maximal therapeutic benefit, and predict whether a therapy will result in an adverse response and should be avoided in a given individual. Pharmacogenetic studies of the glucocorticoid, leukotriene, and β2-adrenergic receptor pathways have focused on candidate genes within these pathways and, in addition to a small number of genome-wide association studies, have identified genetic loci associated with therapeutic responsiveness. This review summarizes these pharmacogenetic discoveries and the future of genetic profiles for personalized medicine in asthma. The benefit of a personalized, tailored approach to health care delivery is needed in the development of expensive biologic drugs directed at a specific biologic pathway. Prior pharmacogenetic discoveries, in combination with additional variants identified in future studies, will form the basis for future genetic profiles for personalized tailored approaches to maximize therapeutic benefit for an individual asthmatic while minimizing the risk for adverse events. PMID:25691813

What is needed to incorporate clinical pharmacogenetic tests into the practice of psychopharmacotherapy?

PubMed

de Leon, Jose; Spina, Edoardo

2016-01-01

This editorial considers two questions in psychopharmacotherapy: 1) What is needed to market pharmacogenetic tests in the US, since the US appears to lead other countries? and 2) What is needed for US-marketed pharmacogenetic tests to be incorporated by prescribers into long-term practice? US marketing of pharmacogenetic tests requires 1) understanding the pharmacological complexity of drug response, 2) modifying the oversight of non-FDA regulatory agencies, 3) clarifying the FDA's role and 4) promoting innovative marketing. The incorporation of pharmacogenetic tests into long-term practice requires 1) not jeopardizing pharmacogenetic testing by short-sighted marketing of non-validated tests, 2) educating prescribers about benefits, 3) educating patients about limitations and 4) considering the differences between isolated testing and generalized testing incorporating big data.

A nationwide survey of pharmacists' perception of pharmacogenetics in the context of a clinical decision support system containing pharmacogenetics dosing recommendations.

PubMed

Bank, Paul Cd; Swen, Jesse J; Guchelaar, Henk-Jan

2017-02-01

To benchmark Dutch pharmacists knowledge, experience and attitudes toward pharmacogenetics (PGx) with a specific focus on the effects of awareness of the Dutch Pharmacogenetics Working Group guidelines. A web-based survey containing 41 questions was sent to all certified Dutch pharmacists. A total of 667 pharmacists completed the survey (18.8%). Virtually all responders believed in the concept of PGx (99.7%). However, only 14.7% recently ordered a PGx test (≤6 months), 14.1% felt adequately informed and 88.8% would like to receive additional training on PGx. Being aware of the Dutch Pharmacogenetics Working Group guidelines did not have any significant effect on knowledge or adoption of PGx. Dutch pharmacists are very positive toward PGx. However, test adoption is low and additional training is warranted.

The contribution of pharmacogenetics to pharmacovigilance.

PubMed

Bondon-Guitton, Emmanuelle; Despas, Fabien; Becquemont, Laurent

2016-04-01

Since the beginning of this century, information on pharmacogenetics appears in the summary of product characteristics (SPC) of drugs. Pharmacogenetic tests particularly concern the enzymes involved in the metabolism of drugs, among which P450 cytochromes. Some patients known as poor metabolisers eliminate some drugs more slowly, causing overdoses and adverse drug reactions (ADRs). The best-known examples are AVK and VKORC1-CYP2C9 or clopidogrel and CYP2C19. In the USA, the tests are recommended before the introduction of these drugs to prevent the occurrence of ADRs. Other tests are also commonly performed to address the toxicity of certain anticancer drugs (DPYD-capecitabine, UGT1A1-irinotecan, TPMT 6-mercaptopurine). Pharmacogenetic testing is also available to identify HLA loci that are very strongly associated with the occurrence of immuno-allergic reactions to a specific drug. The best-known example is HLA-B*5701, strongly associated with hypersensitivity to abacavir, and this test is now always prescribed before the instatement of this drug. Copyright © 2016 Société française de pharmacologie et de thérapeutique. Published by Elsevier Masson SAS. All rights reserved.

Advances and challenges in hereditary cancer pharmacogenetics.

PubMed

Cascorbi, Ingolf; Werk, Anneke Nina

2017-01-01

Cancer pharmacogenetics usually considers tumor-specific targets. However, hereditary genetic variants may interfere with the pharmacokinetics of antimetabolites and other anti-cancer drugs, which may lead to severe adverse events. Areas covered: Here, the impact of hereditary genes considered in drug labels such as thiopurine S-methyltransferase (TPMT), UDP-glucuronosyltransferase 1A1 (UTG1A1) and dihydropyrimidine dehydrogenase (DPYD) are discussed with respect to guidelines of the Clinical Pharmacogenetics Implementation Consortium (CPIC). Moreover, the association between genetic variants of drug transporters with the clinical outcome is comprehensively discussed. Expert opinion: Precision therapy in the field of oncology is developing tremendously. There are a number of somatic tumor genetic markers that are indicative for treatment with anti-cancer drugs. By contrast, for some hereditary variants, recommendations have been developed. Although we have vast knowledge on the association between drug transporter variants and clinical outcome, the overall data is inconsistent and the predictability of the related phenotype is low. Further developments in research may lead to the discovery of rare, but functionally relevant single nucleotide polymorphisms and a better understanding of multiple genomic, epigenomic as well as phenotypic factors, contributing to drug response in malignancies.

Pharmacogenetics: A strategy for personalized medicine for autoimmune diseases.

PubMed

Tavakolpour, S; Darvishi, M; Ghasemiadl, M

2018-03-01

For many years, a considerable number of patients with autoimmune diseases (ADs) have suffered from a lack of drug response and drug-related toxicity. Despite the emergence of new therapeutic options such as biological agents, patients continue to struggle with these problems. Unfortunately, new challenges, including the paradoxical effects of biological drugs, have complicated the situation. In recent decades, efforts have been made to predict drug response as well as drug-related side effects. Thanks to the many advances in genetics, evaluation of markers to predict drug response/toxicity before the initiation of treatment may be an avenue toward personalizing treatments. Implementing pharmacogenetics and pharmacogenomics in the clinic could improve clinical care; however, obstacles remain to effective personalized medicine for ADs. The present study attempted to clarify the concept of pharmacogenetics/pharmacogenomics for ADs. After an overview on the pathogenesis of the most common types of treatments, this paper focuses on pharmacogenetic studies related to the selected ADs. Bridging the gap between pharmacogenetics and personalized medicine is also discussed. Moreover, the advantages, disadvantages and recommendations related to making personalized medicine practical for ADs have been addressed. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Pharmacogenetics of drug-metabolizing enzymes in US Hispanics

PubMed Central

Duconge, Jorge; Cadilla, Carmen L.; Ruaño, Gualberto

2015-01-01

Although the Hispanic population is continuously growing in the United States, they are underrepresented in pharmacogenetic studies. This review addresses the need for compiling available pharmacogenetic data in US Hispanics, discussing the prevalence of clinically relevant polymorphisms in pharmacogenes encoding for drug-metabolizing enzymes. CYP3A5*3 (0.245–0.867) showed the largest frequency in a US Hispanic population. A higher prevalence of CYP2C9*3, CYP2C19*4, and UGT2B7 IVS1+985 A>Gwas observed in US Hispanic vs. non-Hispanic populations. We found interethnic and intraethnic variability in frequencies of genetic polymorphisms for metabolizing enzymes, which highlights the need to define the ancestries of participants in pharmacogenetic studies. New approaches should be integrated in experimental designs to gain knowledge about the clinical relevance of the unique combination of genetic variants occurring in this admixed population. Ethnic subgroups in the US Hispanic population may harbor variants that might be part of multiple causative loci or in linkage-disequilibrium with functional variants. Pharmacogenetic studies in Hispanics should not be limited to ascertain commonly studied polymorphisms that were originally identified in their parental populations. The success of the Personalized Medicine paradigm will depend on recognizing genetic diversity between and within US Hispanics and the uniqueness of their genetic backgrounds. PMID:25431893

Challenges and pitfalls in the introduction of pharmacogenetics for cancer.

PubMed

Loh, Marie; Soong, Richie

2011-08-01

There have been several success stories in the field of pharmacogenetics in recent years, including the analysis of HER2 amplification for trastuzumab selection in breast cancer and VKORC1 genotyping for warfarin dosing in thrombosis. Encouraging results from these studies suggest that genetic factors may indeed be important determinants of drug response and toxicity for at least some drugs. However, to apply pharmacogenetics appropriately, a thorough understanding of the scope and limitations of this field is required. The challenges include an appreciation of biological variability, logistical issues pertaining to the proper management of information, the need for robust methods and adequate sample quality with well-designed workflows. At the same time, the economics of pharmacogenetic testing from the perspective of clinicians, patients, governments, insurance companies and pharmaceutical companies will play an important role in determining its future use. Ethical considerations such as informed consent and patient privacy, as well as the role of regulatory bodies in addressing these issues, must be fully understood. Only once these issues are properly dealt with can the full benefits of pharmacogenetics begin to be realised.

Clopidogrel and warfarin pharmacogenetic tests: what is the evidence for use in clinical practice?

PubMed Central

Shahin, Mohamed H.A.; Johnson, Julie A.

2013-01-01

Purpose of review To review the most promising genetic markers associated with the variability in the safety or efficacy of warfarin and clopidogrel and highlight the verification and validation initiatives for translating clopidogrel and warfarin pharmacogenetic tests to clinical practice. Recent findings Rapid advances in pharmacogenetics, continuous decrease in genotyping cost, development of point-of-care devices and the newly established clinical genotyping programs at several institutions hold the promise of individualizing clopidogrel and warfarin based on genotype. Guidelines have been established to assist clinicians in prescribing clopidogrel or warfarin dose based on genotype. However, the clinical utility of clopidogrel and warfarin is still limited. Accordingly, large randomized clinical trials are underway to define the role of clopidogrel and warfarin pharmacogenetics in clinical practice. Summary Pharmacogenetics has offered compelling evidence toward the individualization of clopidogrel and warfarin therapies. The rapid advances in technology make the clinical implementation of clopidogrel and warfarin pharmacogenetics possible. The clinical genotyping programs and the ongoing clinical trials will help in overcoming some of the barriers facing the clinical implementation of clopidogrel and warfarin pharmacogenetics. PMID:23478884

Evaluation of pharmacy students' knowledge and perceptions of pharmacogenetics before and after a simulation activity.

PubMed

Patel, Radha V; Chudow, Melissa; Vo, Teresa T; Serag-Bolos, Erini S

The purpose of this study was to evaluate students' knowledge and perceptions of the clinical application of pharmacogenetics through a simulation activity and to assess communication of pharmacogenetic-guided treatment recommendations utilizing standardized patients. Third-year students in the four-year doctor of pharmacy (PharmD) program at University of South Florida College of Pharmacy completed a pharmacogenetics simulation involving a patient case review, interpretation of pharmacogenetic test results, completion of a situation, background, assessment, recommendation (SBAR) note with drug therapy recommendations, and patient counseling. Voluntary assessments were completed before and after the simulation, which included demographics, knowledge, and perceptions of students' ability to interpret and communicate pharmacogenetic results. Response rates for the pre- and post-simulation assessments were 109 (98%) and 104 (94%), respectively. Correct responses in application-type questions improved after the simulation (74%) compared to before the simulation (44%, p < 0.01). Responses to perception questions shifted towards "strongly agree" or "agree" after the simulation (p < 0.01). The simulation gave students an opportunity to apply pharmacogenetics knowledge and allowed them to gain an appreciation of pharmacists' roles within the pharmacogenetics field. Copyright © 2017 Elsevier Inc. All rights reserved.

Comparison of Nine Statistical Model Based Warfarin Pharmacogenetic Dosing Algorithms Using the Racially Diverse International Warfarin Pharmacogenetic Consortium Cohort Database

PubMed Central

Liu, Rong; Li, Xi; Zhang, Wei; Zhou, Hong-Hao

2015-01-01

Objective Multiple linear regression (MLR) and machine learning techniques in pharmacogenetic algorithm-based warfarin dosing have been reported. However, performances of these algorithms in racially diverse group have never been objectively evaluated and compared. In this literature-based study, we compared the performances of eight machine learning techniques with those of MLR in a large, racially-diverse cohort. Methods MLR, artificial neural network (ANN), regression tree (RT), multivariate adaptive regression splines (MARS), boosted regression tree (BRT), support vector regression (SVR), random forest regression (RFR), lasso regression (LAR) and Bayesian additive regression trees (BART) were applied in warfarin dose algorithms in a cohort from the International Warfarin Pharmacogenetics Consortium database. Covariates obtained by stepwise regression from 80% of randomly selected patients were used to develop algorithms. To compare the performances of these algorithms, the mean percentage of patients whose predicted dose fell within 20% of the actual dose (mean percentage within 20%) and the mean absolute error (MAE) were calculated in the remaining 20% of patients. The performances of these techniques in different races, as well as the dose ranges of therapeutic warfarin were compared. Robust results were obtained after 100 rounds of resampling. Results BART, MARS and SVR were statistically indistinguishable and significantly out performed all the other approaches in the whole cohort (MAE: 8.84–8.96 mg/week, mean percentage within 20%: 45.88%–46.35%). In the White population, MARS and BART showed higher mean percentage within 20% and lower mean MAE than those of MLR (all p values < 0.05). In the Asian population, SVR, BART, MARS and LAR performed the same as MLR. MLR and LAR optimally performed among the Black population. When patients were grouped in terms of warfarin dose range, all machine learning techniques except ANN and LAR showed significantly

PREEMPTIVE PHARMACOGENETIC TESTING: EXPLORING THE KNOWLEDGE AND PERSPECTIVES OF UNITED STATES PAYERS

PubMed Central

Keeling, Nicholas J.; Rosenthal, Meagen M.; West-Strum, Donna; Patel, Amit; Haidar, Cyrine E.; Hoffman, James M.

2017-01-01

PURPOSE Preemptive pharmacogenetic testing aims to optimize medication use by having genetic information at the point of prescribing. Payers’ decisions influence implementation of this technology. We investigated U.S. payers’ knowledge, awareness, and perspectives on preemptive pharmacogenetic testing. METHODS A qualitative study was conducted using semi-structured interviews. Participants were screened for eligibility through an online survey. A blended inductive and deductive approach was used to analyze the transcripts. Two authors conducted an iterative reading process to code and categorize the data. RESULTS Medical or pharmacy directors from 14 payer organizations covering 122 million U.S. lives were interviewed. Three concept domains and ten dimensions were developed. Key findings include: clinical utility concerns and limited exposure to preemptive germline testing, continued preference for outcomes from randomized controlled trials, interest in guideline development, importance of demonstrating an impact on clinical decision making, concerns of downstream costs and benefit predictability, and the impact of public stakeholders such as the FDA and CMS. CONCLUSION Both barriers and potential facilitators exist to developing cohesive reimbursement policy for pharmacogenetics, and there are unique challenges for the preemptive testing model. Prospective outcome studies, more precisely defining target populations, and predictive economic models are important considerations for future research. PMID:29261180

Pharmacogenetics in Europe: barriers and opportunities.

PubMed

Gurwitz, D; Zika, E; Hopkins, M M; Gaisser, S; Ibarreta, D

2009-01-01

This paper reviews the current situation in the field of pharmacogenetics/pharmacogenomics (PGx) in Europe. High expectations surrounding the clinical application of PGx remain largely unmet, as only a limited number of such applications have actually reached the market and clinical practice. Thus, the potential impact of PGx-based diagnostics on healthcare and its socio-economic implications are still unclear. With the aim of shedding some light on these uncertainties, the Institute for Prospective Technological Studies (IPTS) of the European Commission's Joint Research Centre (JRC) has conducted a review of the 'state of the art' and a further analysis on the use of pharmacogenetics diagnostics for preventing toxic drug reactions and improving drug efficacy in Europe. The paper presents highlights from the JRC-IPTS studies and discusses possibilities for improving translation of PGx research in Europe by comparing some experiences in the USA. We also illustrate the related barriers for the clinical uptake of PGx in Europe with specific case-studies. Most of the barriers identified extend beyond the European context. This reflects the global problems of scarcity of data demonstrating proven clinical validity or utility and favorable cost-effectiveness studies to support the clinical application of PGx diagnostic tests in the clinical setting. Another key barrier is the lack of incentives for the private sector to invest in the development and licensing of PGx diagnostic tests for improving the safety and efficacy of out-of-patent drugs. It therefore seems that one key aspect where policy can affect the clinical uptake of PGx is via sustaining large-scale industry-academia collaborations for developing and proving the utility of PGx diagnostics. Copyright 2009 S. Karger AG, Basel.

From evidence based medicine to mechanism based medicine. Reviewing the role of pharmacogenetics.

PubMed

Wilffert, Bob; Swen, Jesse; Mulder, Hans; Touw, Daan; Maitland-Van der Zee, Anke-Hilse; Deneer, Vera

2013-06-01

The translation of evidence based medicine to a specific patient presents a considerable challenge. We present by means of the examples nortriptyline, tramadol, clopidogrel, coumarins, abacavir and antipsychotics the discrepancy between available pharmacogenetic information and its implementation in daily clinical practice. Literature review. A mechanism based approach may be helpful to personalize medicine for the individual patient to which pharmacogenetics may contribute significantly. The lack of consistency in what we accept in bioequivalence and in pharmacogenetics of drug metabolising enzymes is discussed and illustrated with the example of nortriptyline. The impact of pharmacogenetics on examples like tramadol, clopidogrel, coumarins and abacavir is described. Also the present status of the polymorphisms of 5-HT2A and C receptors in antipsychotic-induced weight gain is presented as a pharmacodynamic example with until now a greater distance to clinical implementation. The contribution of pharmacogenetics to tailor-made pharmacotherapy, which especially might be of value for patients deviating from the average, has not yet reached the position it seems to deserve.

Pharmacogenetics of tyrosine kinase inhibitors in gastrointestinal stromal tumor and chronic myeloid leukemia.

PubMed

Ravegnini, Gloria; Sammarini, Giulia; Angelini, Sabrina; Hrelia, Patrizia

2016-07-01

Gastrointestinal stromal tumors (GIST) and chronic myeloid leukemia (CML) are two tumor types deeply different from each other. Despite the differences, these disorders share treatment with tyrosine kinase inhibitor imatinib. Despite the success of imatinib, the response rates vary among different individuals and pharmacogenetics may play an important role in the final clinical outcome. In this review, the authors provide an overview of the pharmacogenetic literature analyzing the role of polymorphisms in both GIST and CML treatment efficacy and toxicity. So far, several polymorphisms influencing the pharmacokinetic determinants of imatinib have been identified. However, the data are not yet conclusive enough to translate pharmacogenetic tests in clinical practice. In this context, the major obstacles to pharmacogenetic test validation are represented by the small sample size of most studies, ethnicity and population admixture as confounding source, and uncertainty related to genetic variants analyzed. In conclusion, a combination of different theoretical approaches, experimental model systems and statistical methods is clearly needed, in order to appreciate pharmacogenetics applied to clinical practice in the near future.

Characterization of 137 Genomic DNA Reference Materials for 28 Pharmacogenetic Genes

PubMed Central

Pratt, Victoria M.; Everts, Robin E.; Aggarwal, Praful; Beyer, Brittany N.; Broeckel, Ulrich; Epstein-Baak, Ruth; Hujsak, Paul; Kornreich, Ruth; Liao, Jun; Lorier, Rachel; Scott, Stuart A.; Smith, Chingying Huang; Toji, Lorraine H.; Turner, Amy; Kalman, Lisa V.

2017-01-01

Pharmacogenetic testing is increasingly available from clinical laboratories. However, only a limited number of quality control and other reference materials are currently available to support clinical testing. To address this need, the Centers for Disease Control and Prevention–based Genetic Testing Reference Material Coordination Program, in collaboration with members of the pharmacogenetic testing community and the Coriell Cell Repositories, has characterized 137 genomic DNA samples for 28 genes commonly genotyped by pharmacogenetic testing assays (CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4, CYP3A5, CYP4F2, DPYD, GSTM1, GSTP1, GSTT1, NAT1, NAT2, SLC15A2, SLC22A2, SLCO1B1, SLCO2B1, TPMT, UGT1A1, UGT2B7, UGT2B15, UGT2B17, and VKORC1). One hundred thirty-seven Coriell cell lines were selected based on ethnic diversity and partial genotype characterization from earlier testing. DNA samples were coded and distributed to volunteer testing laboratories for targeted genotyping using a number of commercially available and laboratory developed tests. Through consensus verification, we confirmed the presence of at least 108 variant pharmacogenetic alleles. These samples are also being characterized by other pharmacogenetic assays, including next-generation sequencing, which will be reported separately. Genotyping results were consistent among laboratories, with most differences in allele assignments attributed to assay design and variability in reported allele nomenclature, particularly for CYP2D6, UGT1A1, and VKORC1. These publicly available samples will help ensure the accuracy of pharmacogenetic testing. PMID:26621101

Pharmacogenetics of posttransplant diabetes mellitus.

PubMed

Lancia, P; Adam de Beaumais, T; Jacqz-Aigrain, E

2017-06-01

Many factors (physiological, pathological, environmental or genetic) are associated with variability in drug effect. Most patients respond to a standard treatment but the drug may be ineffective or toxic. In this review, we focused on genetic markers of posttransplant diabetes mellitus (PTDM) after renal transplantation, a frequent complication of immunosuppressive therapy and important risk factor of graft loss and mortality. An initial literature search identified 100 publications and among them 32 association studies were retrieved under 'Pharmacogenetics and PTDM'. Thirty-five variants in 25 genes with an impact on insulin secretion, disposition or effect were significantly associated with PTDM. The population studied, immunosuppressive regimen, follow-up, PTDM diagnostic and genetic variations tested were highly variable between studies. Although pharmacogenetic biomarkers are key tools of great promise for preventing toxicities and improving event-free survival rates, replication studies are required to select validated biomarkers linked to the occurrence of PTDM and select appropriate immusuppressive treatment to improve renal graft and patient outcome.

Pharmacogenetic Association of the Galanin Receptor (GALR1) SNP rs2717162 with Smoking Cessation

PubMed Central

Gold, Allison B; Wileyto, E Paul; Lori, Adriana; Conti, David; Cubells, Joseph F; Lerman, Caryn

2012-01-01

Galanin modulates dopaminergic neurotransmission in the mesolimbic dopamine system, thereby influencing the rewarding effects of nicotine. Variants in the galanin receptor 1 (GALR1) gene have been associated with retrospective craving severity and heaviness of smoking in prior research. We investigated pharmacogenetic associations of the previously studied GALR1 polymorphism, rs2717162, in 1217 smokers of European ancestry who participated in one of three pharmacogenetic smoking cessation clinical trials and were treated with nicotine patch (n=623), nicotine nasal spray (n=189), bupropion (n=213), or placebo (n=192). The primary endpoint was abstinence (7-day point prevalence, biochemically confirmed) at the end of treatment. Cravings to smoke were assessed on the target quit day (TQD). The longitudinal regression model revealed a significant genotype by treatment interaction (P=0.03). There was a reduced odds of quitting success with the presence of at least one minor (C) allele in the bupropion-treated group (OR=0.43; 95% CI=0.22–0.77; P=0.005) but equivalent quit rates by genotype in the nicotine-replacement therapy groups. This genotype by treatment interaction was reproduced in a Cox regression model of time to relapse (P=0.04). In the bupropion trial, smokers carrying the C allele also reported more severe TQD cravings. Further research to identify functional variants in GALR1 and to replicate pharmacogenetic associations is warranted. PMID:22373943

Clinical implementation of pharmacogenetics in kidney transplantation: calcineurin inhibitors in the starting blocks.

PubMed

Elens, Laure; Bouamar, Rachida; Shuker, Nauras; Hesselink, Dennis A; van Gelder, Teun; van Schaik, Ron H N

2014-04-01

Pharmacogenetics has generated many expectations for its potential to individualize therapy proactively and improve medical care. However, despite the huge amount of reported genetic associations with either pharmacokinetics or pharmacodynamics of drugs, the translation into patient care is still slow. In fact, strong evidence for a substantial clinical benefit of pharmacogenetic testing is still limited, with a few exceptions. In kidney transplantation, established pharmacogenetic discoveries are being investigated for application in the clinic to improve efficacy and to limit toxicity associated with the use of immunosuppressive drugs, especially the frequently used calcineurin inhibitors (CNIs) tacrolimus and ciclosporin. The purpose of the present review is to picture the current status of CNI pharmacogenetics and to discuss the most promising leads that have been followed so far. © 2013 The British Pharmacological Society.

The promise of pharmacogenetics: assessing the prospects for disease and patient stratification.

PubMed

Smart, Andrew; Martin, Paul

2006-09-01

Pharmacogenetics is an emerging biotechnology concerned with understanding the genetic basis of drug response, and promises to transform the development, marketing and prescription of medicines. This paper is concerned with analysing the move towards segmented drug markets, which is implicit in the commercial development of pharmacogenetics. It is claimed that in future who gets a particular drug will be determined by their genetic make up. Drawing on ideas from the sociology of expectations we examine how pharmaceutical and biotechnology companies are constructing, responding to and realising particular 'visions' or expectations of pharmacogenetics and market stratification. We argue that the process of market segmentation remains uncertain, but that the outcome will be fashioned according to the convergence and divergence of the interests of key commercial actors. Qualitative data based both on interviews with industry executives and company documentation will be used to explore how different groups of companies are developing pharmacogenetics in distinct ways, and what consequences these different pathways might have for both clinical practice and health policy. In particular, the analysis will show a convergence of interests between biotechnology and pharmaceutical companies for creating segmented markets for new drugs, but a divergence of interest in segmenting established markets. Whilst biotechnology firms have a strong incentive to innovate, the pharmaceutical industry has no commercial interest in segmenting markets for existing products. This has important implications, as many of the claimed public health benefits of pharmacogenetics will derive from changing the prescribing of existing medicines. One significant implication of this is that biotechnology companies who wish to apply pharmacogenetics to existing medicines will have to explore an alternative convergence of interests with healthcare payers and providers (health insurers, HMOs, MCOs and

Pharmacogenetics in type 2 diabetes: precision medicine or discovery tool?

PubMed

Florez, Jose C

2017-05-01

In recent years, technological and analytical advances have led to an explosion in the discovery of genetic loci associated with type 2 diabetes. However, their ability to improve prediction of disease outcomes beyond standard clinical risk factors has been limited. On the other hand, genetic effects on drug response may be stronger than those commonly seen for disease incidence. Pharmacogenetic findings may aid in identifying new drug targets, elucidate pathophysiology, unravel disease heterogeneity, help prioritise specific genes in regions of genetic association, and contribute to personalised or precision treatment. In diabetes, precedent for the successful application of pharmacogenetic concepts exists in its monogenic subtypes, such as MODY or neonatal diabetes. Whether similar insights will emerge for the much more common entity of type 2 diabetes remains to be seen. As genetic approaches advance, the progressive deployment of candidate gene, large-scale genotyping and genome-wide association studies has begun to produce suggestive results that may transform clinical practice. However, many barriers to the translation of diabetes pharmacogenetic discoveries to the clinic still remain. This perspective offers a contemporary overview of the field with a focus on sulfonylureas and metformin, identifies the major uses of pharmacogenetics, and highlights potential limitations and future directions.

Fluoropyrimidine and platinum toxicity pharmacogenetics: an umbrella review of systematic reviews and meta-analyses.

PubMed

Campbell, Jared M; Bateman, Emma; Peters, Micah Dj; Bowen, Joanne M; Keefe, Dorothy M; Stephenson, Matthew D

2016-03-01

Fluoropyrimidine (FU) and platinum-based chemotherapies are greatly complicated by their associated toxicities. This umbrella systematic review synthesized all systematic reviews that investigated associations between germline variations and toxicity, with the aim of informing personalized medicine. Systematic reviews are important in pharmacogenetics where false positives are common. Four systematic reviews were identified for FU-induced toxicity and three for platinum. Polymorphisms of DPYD and TYMS, but not MTHFR, were statistically significantly associated with FU-induced toxicity (although only DPYD had clinical significance). For platinum, GSTP1 was found to not be associated with toxicity. This umbrella systematic review has synthesized the best available evidence on the pharmacogenetics of FU and platinum toxicity. It provides a useful reference for clinicians and identifies important research gaps.

Present status and perspective of pharmacogenetics in Mexico.

PubMed

Cuautle-Rodríguez, Patricia; Llerena, Adrián; Molina-Guarneros, Juan

2014-01-01

Drug costs account for up to 24% of the country's health expenditure and there are 13,000 registered drugs being prescribed. Diabetes is the main cause of death in the country, with over 85% of diabetic patients currently under drug treatment. The importance of knowing interindividual variability in drug metabolism on Mexican populations is thus evident. The purpose of this article is to provide an overlook of the current situation of pharmacogenetic research in Mexico, focusing on drug-metabolizing enzymes, and the possibility of developing a phenotyping cocktail for Mexican populations. So far, 21 pharmacogenetic studies on Mexican population samples (Mestizos and Amerindian) have been published. These have reported interindividual variability through phenotyping and/or genotyping cytochromes: CYP2D6, 2C19, 2C9, 2E1, and phase II enzymes UGT and NAT2. Some cytochromes with important clinical implications have not yet been phenotyped in Mexican populations. The development of a cocktail adapted to them could be a significant contribution to a larger knowledge on drug response variability at a lower price and shorter time. There are validated phenotyping cocktails that present several practical advantages, being valuable, safe, and inexpensive tools in drug metabolism characterization, which require only a single experiment to provide information on several cytochrome activities.

Preemptive clinical pharmacogenetics implementation: current programs in five US medical centers.

PubMed

Dunnenberger, Henry M; Crews, Kristine R; Hoffman, James M; Caudle, Kelly E; Broeckel, Ulrich; Howard, Scott C; Hunkler, Robert J; Klein, Teri E; Evans, William E; Relling, Mary V

2015-01-01

Although the field of pharmacogenetics has existed for decades, practioners have been slow to implement pharmacogenetic testing in clinical care. Numerous publications describe the barriers to clinical implementation of pharmacogenetics. Recently, several freely available resources have been developed to help address these barriers. In this review, we discuss current programs that use preemptive genotyping to optimize the pharmacotherapy of patients. Array-based preemptive testing includes a large number of relevant pharmacogenes that impact multiple high-risk drugs. Using a preemptive approach allows genotyping results to be available prior to any prescribing decision so that genomic variation may be considered as an inherent patient characteristic in the planning of therapy. This review describes the common elements among programs that have implemented preemptive genotyping and highlights key processes for implementation, including clinical decision support.

Pharmacogenetics of Antipsychotics

PubMed Central

Brandl, Eva J; Kennedy, James L; Müller, Daniel J

2014-01-01

Objective: During the past decades, increasing efforts have been invested in studies to unravel the influence of genetic factors on antipsychotic (AP) dosage, treatment response, and occurrence of adverse effects. These studies aimed to improve clinical care by predicting outcome of treatment with APs and thus allowing for individualized treatment strategies. We highlight most important findings obtained through both candidate gene and genome-wide association studies, including pharmacokinetic and pharmacodynamic factors. Methods: We reviewed studies on pharmacogenetics of AP response and adverse effects published on PubMed until early 2012. Owing to the high number of published studies, we focused our review on findings that have been replicated in independent studies or are supported by meta-analyses. Results: Most robust findings were reported for associations between polymorphisms of the cytochrome P450 system, the dopamine and the serotonin transmitter systems, and dosage, treatment response, and adverse effects, such as AP-induced weight gain or tardive dyskinesia. These associations were either detected for specific medications or for classes of APs. Conclusion: First promising and robust results show that pharmacogenetics bear promise for a widespread use in future clinical practice. This will likely be achieved by developing algorithms that will include many genetic variants. However, further investigation is warranted to replicate and validate previous findings, as well as to identify new genetic variants involved in AP response and for replication of existing findings. PMID:24881126

Pharmacogenetics and Predictive Testing of Drug Hypersensitivity Reactions.

PubMed

Böhm, Ruwen; Cascorbi, Ingolf

2016-01-01

Adverse drug reactions adverse drug reaction (ADR) occur in approximately 17% of patients. Avoiding ADR is thus mandatory from both an ethical and an economic point of view. Whereas, pharmacogenetics changes of the pharmacokinetics may contribute to the explanation of some type A reactions, strong relationships of genetic markers has also been shown for drug hypersensitivity belonging to type B reactions. We present the classifications of ADR, discuss genetic influences and focus on delayed-onset hypersensitivity reactions, i.e., drug-induced liver injury, drug-induced agranulocytosis, and severe cutaneous ADR. A guidance how to read and interpret the contingency table is provided as well as an algorithm whether and how a test for a pharmacogenetic biomarker should be conducted.

Pharmacogenetics: has the time come for pharmacists to embrace and implement the science?

PubMed

Beier, Manju T; Panchapagesan, Madhumitha; Carman, Ladd E

2013-11-01

Pharmacogenetics--the study of interindividual differences in medication response as a result of genetic variations--has emerged as a potentially useful tool for individualizing medication regimens for patients. Genetic variations can affect drug disposition inseveral ways, from modifying receptor sensitivities to impacting drug metabolism. Over the last several years, the Food and Drug Administration has been steadily including pharmacogenetic information in drug labeling for several commonly prescribed drugs. Several organizations are attempting to provide evidence-based guidelines for widespread implementation and interpretation. Pharmacists, armed with knowledge of drug metabolism pathways and drug-gene interactions, are uniquely positioned to play an active role in the education, provision, and clinical implementation of pharmacogenetics.

Understanding the pharmacogenetics of selective serotonin reuptake inhibitors.

PubMed

Fabbri, Chiara; Minarini, Alessandro; Niitsu, Tomihisa; Serretti, Alessandro

2014-08-01

The genetic background of antidepressant response represents a unique opportunity to identify biological markers of treatment outcome. Encouraging results alternating with inconsistent findings made antidepressant pharmacogenetics a stimulating but often discouraging field that requires careful discussion about cumulative evidence and methodological issues. The present review discusses both known and less replicated genes that have been implicated in selective serotonin reuptake inhibitors (SSRIs) efficacy and side effects. Candidate genes studies and genome-wide association studies (GWAS) were collected through MEDLINE database search (articles published till January 2014). Further, GWAS signals localized in promising genetic regions according to candidate gene studies are reported in order to assess the general comparability of results obtained through these two types of pharmacogenetic studies. Finally, a pathway enrichment approach is applied to the top genes (those harboring SNPs with p < 0.0001) outlined by previous GWAS in order to identify possible molecular mechanisms involved in SSRI effect. In order to improve the understanding of SSRI pharmacogenetics, the present review discusses the proposal of moving from the analysis of individual polymorphisms to genes and molecular pathways, and from the separation across different methodological approaches to their combination. Efforts in this direction are justified by the recent evidence of a favorable cost-utility of gene-guided antidepressant treatment.

Pharmacogenetics: Implications of Race and Ethnicity on Defining Genetic Profiles for Personalized Medicine

PubMed Central

Ortega, Victor E.; Meyers, Deborah A.

2014-01-01

Pharmacogenetics is being used to develop personalized therapies specific to individuals from different ethnic or racial groups. Pharmacogenetic studies to date have been primarily performed in trial cohorts consisting of non-Hispanic whites of European descent. A “bottleneck” or collapse of genetic diversity associated with the first human colonization of Europe during the Upper Paleolithic period, followed by the recent mixing of African, European, and Native American ancestries has resulted in different ethnic groups with varying degrees of genetic diversity. Differences in genetic ancestry may introduce genetic variation which has the potential to alter the therapeutic efficacy of commonly used asthma therapies, for example β2-adrenergic receptor agonists (beta agonists). Pharmacogenetic studies of admixed ethnic groups have been limited to small candidate gene association studies of which the best example is the gene coding for the receptor target of beta agonist therapy, ADRB2. Large consortium-based sequencing studies are using next-generation whole-genome sequencing to provide a diverse genome map of different admixed populations which can be used for future pharmacogenetic studies. These studies will include candidate gene studies, genome-wide association studies, and whole-genome admixture-based approaches which account for ancestral genetic structure, complex haplotypes, gene-gene interactions, and rare variants to detect and replicate novel pharmacogenetic loci. PMID:24369795

The role of pharmacogenetics in the treatment of chronic hepatitis C infection.

PubMed

Kawaguchi-Suzuki, Marina; Frye, Reginald F

2014-02-01

Hepatitis C virus (HCV) chronically infects 170 million people worldwide. Until recently, combination therapy with peginterferon-α (pegIFN) and ribavirin (RBV) has been the standard of care. However, for many patients, especially those infected with the most common HCV genotype 1 (HCV-1), this treatment has resulted in unsatisfactory treatment response rates. Many clinical factors, including pharmacogenetics, influence the treatment response rate. Genetic variation in the interleukin 28B (IL28B) gene is the major determinant of treatment response, a finding that has been replicated in multiple independent cohorts. This review focuses on the association between pharmacogenetics and conventional pegIFN/RBV therapy in patients infected with HCV non-genotype 1; patients reinfected with HCV after liver transplantation; and patients coinfected with HCV and human immunodeficiency virus. We also review the pharmacogenetic data for boceprevir and telaprevir triple therapy in patients with HCV-1 infection, as well as viral genomic polymorphisms and genetic variants that may protect against anemia. Pharmacogenetic information offers a personalized medicine approach to help clinicians and patients make better informed decisions to maximize response and minimize toxicity for the treatment of chronic HCV infection. © 2013 Pharmacotherapy Publications, Inc.

A systematic review on pharmacogenetics in cardiovascular disease: is it ready for clinical application?

PubMed

Verschuren, Jeffrey J W; Trompet, Stella; Wessels, Judith A M; Guchelaar, Henk-Jan; de Maat, Moniek P M; Simoons, Maarten L; Jukema, J Wouter

2012-01-01

Pharmacogenetics is the search for heritable genetic polymorphisms that influence responses to drug therapy. The most important application of pharmacogenetics is to guide choosing agents with the greatest potential of efficacy and smallest risk of adverse drug reactions. Many studies focusing on drug-gene interactions have been published in recent years, some of which led to adaptation of FDA recommendations, indicating that we are on the verge of the clinical application of genetic information in drug therapy. This systematic review provides a comprehensive overview of the current knowledge on pharmacogenetics of all major drug classes currently used in the treatment of cardiovascular diseases.

Pharmacogenetics of ribavirin-induced anemia in hepatitis C.

PubMed

Ampuero, Javier; Romero-Gómez, Manuel

2016-09-01

Pharmacogenetics assesses inherited genetic differences in drug metabolic pathways and its role in medicine is growing. Ribavirin (RBV) and peginterferon were the standard of care therapy in hepatitis C virus infection during 15 years, with the addition of first-generation protease inhibitors at the beginning of 2010s. New direct-acting agents are the new standard of care, but RBV remains important in some scenarios. The main adverse effect of RBV is anemia, which requires dose reduction and even stopping treatment in some patients. Pharmacogenetics has identified ITPA and SLC28/29 genes to be closely related to RBV-induced anemia. The routine evaluation of these genes could help to identify those patients at risk of developing anemia during the hepatitis C virus treatment.

[Pharmacogenetics in the treatment of tobacco addiction].

PubMed

Quaak, M; van Schooten, F J; van Schayck, C P

2013-01-01

Smokers vary in their genetic susceptibility to become addicted to smoking and probably also in their reaction to smoking cessation pharmacotherapies. To provide an overview of the developments on the pharmacogenetics of the treatment of tobacco addiction. Review article describing the biological processes associated with tobacco addiction, and the influence of genetic variants on smoking behavior and the efficacy of smoking cessation therapies. Several (combinations of) genetic variants in smoking-related genes influence nicotine dependence. Moreover, several genetic variants in smoking- and treatment-related genes seem to influence the efficacy of smoking cessation therapies which are distinctive for the different forms of pharmacotherapy, especially when they have a different mechanism-of-action. Much progress has been made in unraveling the (pharmaco)genetics of tobacco addiction, but much still remains to be done before genetically tailored smoking cessation therapy can be implemented in clinical practice.

Preemptive Clinical Pharmacogenetics Implementation: Current programs in five United States medical centers

PubMed Central

Dunnenberger, Henry M.; Crews, Kristine R.; Hoffman, James M.; Caudle, Kelly E.; Broeckel, Ulrich; Howard, Scott C.; Hunkler, Robert J.; Klein, Teri E.; Evans, William E.; Relling, Mary V.

2015-01-01

Although the field of pharmacogenetics has existed for decades, the implementation of, pharmacogenetic testing in clinical care has been slow. There are numerous publications, describing the barriers to clinical implementation of pharmacogenetics. Recently, several freely, available resources have been developed to help address these barriers. In this review we, discuss current programs that use preemptive genotyping to optimize the pharmacotherapy of, patients. Array-based preemptive testing includes a large number of relevant pharmacogenes, that impact multiple high-risk drugs. Using a preemptive approach allows genotyping results to, be available prior to any prescribing decision so that genomic variation may be considered as, an inherent patient characteristic in the planning of therapy. This review describes the common, elements among programs that have implemented preemptive genotyping and highlights key, processes for implementation, including clinical decision support. PMID:25292429

Benefit of Preemptive Pharmacogenetic Information on Clinical Outcome.

PubMed

Roden, Dan M; Van Driest, Sara L; Mosley, Jonathan D; Wells, Quinn S; Robinson, Jamie R; Denny, Joshua C; Peterson, Josh F

2018-05-01

The development of new knowledge around the genetic determinants of variable drug action has naturally raised the question of how this new knowledge can be used to improve the outcome of drug therapy. Two broad approaches have been taken: a point-of-care approach in which genotyping for specific variant(s) is undertaken at the time of drug prescription, and a preemptive approach in which multiple genetic variants are typed in an individual patient and the information archived for later use when a drug with a "pharmacogenetic story" is prescribed. This review addresses the current state of implementation, the rationale for these approaches, and barriers that must be overcome. Benefits to pharmacogenetic testing are only now being defined and will be discussed. © 2018 American Society for Clinical Pharmacology and Therapeutics.

Can pharmacogenetics explain efficacy and safety of cisplatin pharmacotherapy?

PubMed Central

Roco, Ángela; Cayún, Juan; Contreras, Stephania; Stojanova, Jana; Quiñones, Luis

2014-01-01

Several recent pharmacogenetic studies have investigated the variability in both outcome and toxicity in cisplatin-based therapies. These studies have focused on the genetic variability of therapeutic targets that could affect cisplatin response and toxicity in diverse type of cancer including lung, gastric, ovarian, testicular, and esophageal cancer. In this review, we seek to update the reader in this area of investigation, focusing primarily on DNA reparation enzymes and cisplatin metabolism through Glutathione S-Transferases (GSTs). Current evidence indicates a potential application of pharmacogenetics in therapeutic schemes in which cisplatin is the cornerstone of these treatments. Therefore, a collaborative effort is required to study these molecular characteristics in order to generate a genetic panel with clinical utility. PMID:25452763

Finding influential nodes for integration in brain networks using optimal percolation theory.

PubMed

Del Ferraro, Gino; Moreno, Andrea; Min, Byungjoon; Morone, Flaviano; Pérez-Ramírez, Úrsula; Pérez-Cervera, Laura; Parra, Lucas C; Holodny, Andrei; Canals, Santiago; Makse, Hernán A

2018-06-11

Global integration of information in the brain results from complex interactions of segregated brain networks. Identifying the most influential neuronal populations that efficiently bind these networks is a fundamental problem of systems neuroscience. Here, we apply optimal percolation theory and pharmacogenetic interventions in vivo to predict and subsequently target nodes that are essential for global integration of a memory network in rodents. The theory predicts that integration in the memory network is mediated by a set of low-degree nodes located in the nucleus accumbens. This result is confirmed with pharmacogenetic inactivation of the nucleus accumbens, which eliminates the formation of the memory network, while inactivations of other brain areas leave the network intact. Thus, optimal percolation theory predicts essential nodes in brain networks. This could be used to identify targets of interventions to modulate brain function.

Pharmacogenetic studies update in type 2 diabetes mellitus

PubMed Central

Singh, Shalini; Usman, Kauser; Banerjee, Monisha

2016-01-01

Type 2 diabetes mellitus (T2DM) is a silent progressive polygenic metabolic disorder resulting from ineffective insulin cascading in the body. World-wide, about 415 million people are suffering from T2DM with a projected rise to 642 million in 2040. T2DM is treated with several classes of oral antidiabetic drugs (OADs) viz. biguanides, sulfonylureas, thiazolidinediones, meglitinides, etc. Treatment strategies for T2DM are to minimize long-term micro and macro vascular complications by achieving an optimized glycemic control. Genetic variations in the human genome not only disclose the risk of T2DM development but also predict the personalized response to drug therapy. Inter-individual variability in response to OADs is due to polymorphisms in genes encoding drug receptors, transporters, and metabolizing enzymes for example, genetic variants in solute carrier transporters (SLC22A1, SLC22A2, SLC22A3, SLC47A1 and SLC47A2) are actively involved in glycemic/HbA1c management of metformin. In addition, CYP gene encoding Cytochrome P450 enzymes also play a crucial role with respect to metabolism of drugs. Pharmacogenetic studies provide insights on the relationship between individual genetic variants and variable therapeutic outcomes of various OADs. Clinical utility of pharmacogenetic study is to predict the therapeutic dose of various OADs on individual basis. Pharmacogenetics therefore, is a step towards personalized medicine which will greatly improve the efficacy of diabetes treatment. PMID:27555891

Pharmacogenetics of clozapine treatment response and side-effects in schizophrenia: an update.

PubMed

Sriretnakumar, Venuja; Huang, Eric; Müller, Daniel J

2015-01-01

Clozapine (CLZ) is the most effective treatment for treatment-resistant schizophrenia (SCZ) patients, with potential added benefits of reduction in suicide risk and aggression. However, CLZ is also mainly underused due to its high risk for the potentially lethal side-effect of agranulocytosis as well as weight gain and related metabolic dysregulation. Pharmacogenetics promises to enable the prediction of patient treatment response and risk of adverse effects based on patients' genetics, paving the way toward individualized treatment. This article reviews pharmacogenetics studies of CLZ response and side-effects with a focus on articles from January 2012 to February 2015, as an update to the previous reviews. Pharmacokinetic genes explored primarily include CYP1A2, while pharmacodynamic genes consisted of traditional pharmacogenetic targets such as brain-derived neurotrophic factor as well novel mitochondrial genes, NDUFS-1 and translocator protein. Pharmacogenetics is a promising avenue for individualized medication of CLZ in SCZ, with several consistently replicated gene variants predicting CLZ response and side-effects. However, a large proportion of studies have yielded mixed results. Large-scale Genome-wide association studies (e.g., CRESTAR) and targeted gene studies with standardized designs (response measurements, treatment durations, plasma level monitoring) are required for further progress toward clinical translation. Additionally, in order to improve study quality, we recommend accounting for important confounders, including polypharmacy, baseline measurements, treatment duration, gender, and age at onset.

Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for Pharmacogenetics-Guided Warfarin Dosing: 2017 Update.

PubMed

Johnson, J A; Caudle, K E; Gong, L; Whirl-Carrillo, M; Stein, C M; Scott, S A; Lee, M T; Gage, B F; Kimmel, S E; Perera, M A; Anderson, J L; Pirmohamed, M; Klein, T E; Limdi, N A; Cavallari, L H; Wadelius, M

2017-09-01

This document is an update to the 2011 Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for CYP2C9 and VKORC1 genotypes and warfarin dosing. Evidence from the published literature is presented for CYP2C9, VKORC1, CYP4F2, and rs12777823 genotype-guided warfarin dosing to achieve a target international normalized ratio of 2-3 when clinical genotype results are available. In addition, this updated guideline incorporates recommendations for adult and pediatric patients that are specific to continental ancestry. © 2017 American Society for Clinical Pharmacology and Therapeutics.

Clinical Implementation of Pharmacogenetic Testing in a Hospital of the Spanish National Health System: Strategy and Experience Over 3 Years

PubMed Central

Dapia, Irene; Tong, Hoi Y.; Arias, Pedro; Muñoz, Mario; Tenorio, Jair; Hernández, Rafael; García García, Irene; Gordo, Gema; Ramírez, Elena; Frías, Jesús; Lapunzina, Pablo; Carcas, Antonio J.

2017-01-01

Abstract In 2014, we established a pharmacogenetics unit with the intention of facilitating the integration of pharmacogenetic testing into clinical practice. This unit was centered around two main ideas: i) individualization of clinical recommendations, and ii) preemptive genotyping in risk populations. Our unit is based on the design and validation of a single nucleotide polymorphism (SNP) microarray, which has allowed testing of 180 SNPs associated with drug response (PharmArray), and clinical consultation regarding the results. Herein, we report our experience in integrating pharmacogenetic testing into our hospital and we present the results of the 2,539 pharmacogenetic consultation requests received over the past 3 years in our unit. The results demonstrate the feasibility of implementing pharmacogenetic testing in clinical practice within a national health system. PMID:29193749

A Novel Admixture-Based Pharmacogenetic Approach to Refine Warfarin Dosing in Caribbean Hispanics.

PubMed

Duconge, Jorge; Ramos, Alga S; Claudio-Campos, Karla; Rivera-Miranda, Giselle; Bermúdez-Bosch, Luis; Renta, Jessicca Y; Cadilla, Carmen L; Cruz, Iadelisse; Feliu, Juan F; Vergara, Cunegundo; Ruaño, Gualberto

2016-01-01

This study is aimed at developing a novel admixture-adjusted pharmacogenomic approach to individually refine warfarin dosing in Caribbean Hispanic patients. A multiple linear regression analysis of effective warfarin doses versus relevant genotypes, admixture, clinical and demographic factors was performed in 255 patients and further validated externally in another cohort of 55 individuals. The admixture-adjusted, genotype-guided warfarin dosing refinement algorithm developed in Caribbean Hispanics showed better predictability (R2 = 0.70, MAE = 0.72mg/day) than a clinical algorithm that excluded genotypes and admixture (R2 = 0.60, MAE = 0.99mg/day), and outperformed two prior pharmacogenetic algorithms in predicting effective dose in this population. For patients at the highest risk of adverse events, 45.5% of the dose predictions using the developed pharmacogenetic model resulted in ideal dose as compared with only 29% when using the clinical non-genetic algorithm (p<0.001). The admixture-driven pharmacogenetic algorithm predicted 58% of warfarin dose variance when externally validated in 55 individuals from an independent validation cohort (MAE = 0.89 mg/day, 24% mean bias). Results supported our rationale to incorporate individual's genotypes and unique admixture metrics into pharmacogenetic refinement models in order to increase predictability when expanding them to admixed populations like Caribbean Hispanics. ClinicalTrials.gov NCT01318057.

Cytochrome P450 2C8 pharmacogenetics: a review of clinical studies

PubMed Central

Daily, Elizabeth B; Aquilante, Christina L

2009-01-01

Cytochrome P450 (CYP) 2C8 is responsible for the oxidative metabolism of many clinically available drugs from a diverse number of drug classes (e.g., thiazolidinediones, meglitinides, NSAIDs, antimalarials and chemotherapeutic taxanes). The CYP2C8 enzyme is encoded by the CYP2C8 gene, and several common nonsynonymous polymorphisms (e.g., CYP2C8*2 and CYP2C8*3) exist in this gene. The CYP2C8*2 and *3 alleles have been associated in vitro with decreased metabolism of paclitaxel and arachidonic acid. Recently, the influence of CYP2C8 polymorphisms on substrate disposition in humans has been investigated in a number of clinical pharmacogenetic studies. Contrary to in vitro data, clinical data suggest that the CYP2C8*3 allele is associated with increased metabolism of the CYP2C8 substrates, rosiglitazone, pioglitazone and repaglinide. However, the CYP2C8*3 allele has not been associated with paclitaxel pharmacokinetics in most clinical studies. Furthermore, clinical data regarding the impact of the CYP2C8*3 allele on the disposition of NSAIDs are conflicting and no definitive conclusions can be made at this time. The purpose of this review is to highlight these clinical studies that have investigated the association between CYP2C8 polymorphisms and CYP2C8 substrate pharmacokinetics and/or pharmacodynamics in humans. In this review, CYP2C8 clinical pharmacogenetic data are provided by drug class, followed by a discussion of the future of CYP2C8 clinical pharmacogenetic research. PMID:19761371

Development of a pharmacogenetic-guided warfarin dosing algorithm for Puerto Rican patients.

PubMed

Ramos, Alga S; Seip, Richard L; Rivera-Miranda, Giselle; Felici-Giovanini, Marcos E; Garcia-Berdecia, Rafael; Alejandro-Cowan, Yirelia; Kocherla, Mohan; Cruz, Iadelisse; Feliu, Juan F; Cadilla, Carmen L; Renta, Jessica Y; Gorowski, Krystyna; Vergara, Cunegundo; Ruaño, Gualberto; Duconge, Jorge

2012-12-01

This study was aimed at developing a pharmacogenetic-driven warfarin-dosing algorithm in 163 admixed Puerto Rican patients on stable warfarin therapy. A multiple linear-regression analysis was performed using log-transformed effective warfarin dose as the dependent variable, and combining CYP2C9 and VKORC1 genotyping with other relevant nongenetic clinical and demographic factors as independent predictors. The model explained more than two-thirds of the observed variance in the warfarin dose among Puerto Ricans, and also produced significantly better 'ideal dose' estimates than two pharmacogenetic models and clinical algorithms published previously, with the greatest benefit seen in patients ultimately requiring <7 mg/day. We also assessed the clinical validity of the model using an independent validation cohort of 55 Puerto Rican patients from Hartford, CT, USA (R(2) = 51%). Our findings provide the basis for planning prospective pharmacogenetic studies to demonstrate the clinical utility of genotyping warfarin-treated Puerto Rican patients.

Development of a pharmacogenetic-guided warfarin dosing algorithm for Puerto Rican patients

PubMed Central

Ramos, Alga S; Seip, Richard L; Rivera-Miranda, Giselle; Felici-Giovanini, Marcos E; Garcia-Berdecia, Rafael; Alejandro-Cowan, Yirelia; Kocherla, Mohan; Cruz, Iadelisse; Feliu, Juan F; Cadilla, Carmen L; Renta, Jessica Y; Gorowski, Krystyna; Vergara, Cunegundo; Ruaño, Gualberto; Duconge, Jorge

2012-01-01

Aim This study was aimed at developing a pharmacogenetic-driven warfarin-dosing algorithm in 163 admixed Puerto Rican patients on stable warfarin therapy. Patients & methods A multiple linear-regression analysis was performed using log-transformed effective warfarin dose as the dependent variable, and combining CYP2C9 and VKORC1 genotyping with other relevant nongenetic clinical and demographic factors as independent predictors. Results The model explained more than two-thirds of the observed variance in the warfarin dose among Puerto Ricans, and also produced significantly better ‘ideal dose’ estimates than two pharmacogenetic models and clinical algorithms published previously, with the greatest benefit seen in patients ultimately requiring <7 mg/day. We also assessed the clinical validity of the model using an independent validation cohort of 55 Puerto Rican patients from Hartford, CT, USA (R2 = 51%). Conclusion Our findings provide the basis for planning prospective pharmacogenetic studies to demonstrate the clinical utility of genotyping warfarin-treated Puerto Rican patients. PMID:23215886

Genetic epidemiology of pharmacogenetic variants in South East Asian Malays using whole-genome sequences.

PubMed

Sivadas, A; Salleh, M Z; Teh, L K; Scaria, V

2017-10-01

Expanding the scope of pharmacogenomic research by including multiple global populations is integral to building robust evidence for its clinical translation. Deep whole-genome sequencing of diverse ethnic populations provides a unique opportunity to study rare and common pharmacogenomic markers that often vary in frequency across populations. In this study, we aim to build a diverse map of pharmacogenetic variants in South East Asian (SEA) Malay population using deep whole-genome sequences of 100 healthy SEA Malay individuals. We investigated the allelic diversity of potentially deleterious pharmacogenomic variants in SEA Malay population. Our analysis revealed 227 common and 466 rare potentially functional single nucleotide variants (SNVs) in 437 pharmacogenomic genes involved in drug metabolism, transport and target genes, including 74 novel variants. This study has created one of the most comprehensive maps of pharmacogenetic markers in any population from whole genomes and will hugely benefit pharmacogenomic investigations and drug dosage recommendations in SEA Malays.

Pharmacogenetics and target identification in diabetes.

PubMed

Pearson, Ewan R

2018-02-24

In diabetes, pharmacogenetics can be used both to identify patient subgroups who will have most benefit and/or least harm from a particularly treatment, and to gain insights into the molecular mechanisms of drug action and disease aetiology. There is increasing evidence that genetic variation alters response to diabetes treatments-both in terms of glycaemic response and side effects. This can be seen with dramatic impact on clinical care, in patients with genetic forms of diabetes such as Maturity Onset Diabetes of the Young caused by HNF1A mutations, and Neonatal diabetes due to activating mutations in ABCC8 or KCNJ11. Beyond monogenic diabetes, pharmacogenetic variants have yet to impact on clinical practice, yet the effect sizes (e.g. for metformin intolerance and OCT1 variants; or for metformin action and SLC2A2 variants) are potentially of clinical utility, especially if the genotype is already known at the point of prescribing. Over the next few years, increasing cohort sizes and linkage at scale to electronic medical records will provide considerable potential for stratification and novel target identification in diabetes. Copyright © 2018 Elsevier Ltd. All rights reserved.

Measuring pharmacogenetics in special groups: geriatrics.

PubMed

Seripa, Davide; Panza, Francesco; Daragjati, Julia; Paroni, Giulia; Pilotto, Alberto

2015-07-01

The cytochrome P450 (CYP) enzymes oxidize about 80% of the most commonly used drugs. Older patients form a very interesting clinical group in which an increased prevalence of adverse drug reactions (ADRs) and therapeutic failures (TFs) is observed. Might CYP drug metabolism change with age, and justify the differences in drug response observed in a geriatric setting? A complete overview of the CYP pharmacogenetics with a focus on the epigenetic CYP gene regulation by DNA methylation in the context of advancing age, in which DNA methylation might change. Responder phenotypes consist of a continuum spanning from ADRs to TFs, with the best responders at the midpoint. CYP genetics is the basis of this continuum on which environmental and physiological factors act, modeling the phenotype observed in clinical practice. Physiological age-related changes in DNA methylation, the main epigenetic mechanisms regulating gene expression in humans, results in a physiological decrease in CYP gene expression with advancing age. This may be one of the physiological changes that, together with increased drug use, contributed to the higher prevalence of ADRs and TFs observed in the geriatric setting, thus, making geriatrics a special group for pharmacogenetics.

Clinical Pharmacogenetics Implementation Consortium Guidelines for CYP2C9 and VKORC1 Genotypes and Warfarin Dosing

PubMed Central

Johnson, JA; Gong, L; Whirl-Carrillo, M; Gage, BF; Scott, SA; Stein, CM; Anderson, JL; Kimmel, SE; Lee, MTM; Pirmohamed, M; Wadelius, M; Klein, TE; Altman, RB

2011-01-01

Warfarin is a widely used anticoagulant with a narrow therapeutic index and large interpatient variability in the dose required to achieve target anticoagulation. Common genetic variants in the cytochrome P450-2C9 (CYP2C9) and vitamin K–epoxide reductase complex (VKORC1) enzymes, in addition to known nongenetic factors, account for ~50% of warfarin dose variability. The purpose of this article is to assist in the interpretation and use of CYP2C9 and VKORC1 geno-type data for estimating therapeutic warfarin dose to achieve an INR of 2–3, should genotype results be available to the clinician. The Clinical Pharmacogenetics Implementation Consortium (CPIC) of the National Institutes of Health Pharmacogenomics Research Network develops peer-reviewed gene–drug guidelines that are published and updated periodically on http://www.pharmgkb.org based on new developments in the field.1 PMID:21900891

[Pharmacogenetics--implications for health management and health care economics].

PubMed

Weihrauch, Thomas R

2002-07-15

Pharmacogenetics, which is principally concerned with drug efficacy and safety, will change the way future health care is practiced. The growing understanding of the genetic basis for drug response and use of this knowledge to predict the response of an individual patient offer new opportunities to meet the changing needs of health care systems and the demands placed upon them. For the individual patient, overall quality of life should be higher as physicians will be able to select the most effective and safest treatments for them. However, the cost of patient evaluation will need to be weighed against the additional therapeutic benefit and savings made by avoidance of unnecessary and inadequate drug use and adverse drug responses. Getting the right medicine at the right dose to the patient first time and avoidance of "try and see" prescribing also have the potential to reduce costs due a reduction in number of visits to the physician required to obtain satisfactory treatment. Application of pharmacogenetics to drug development has the potential to streamline the drug development process. Disease and therapy differentiation may lead to stratification of patient groups, and it is possible that the fragmented indications will not represent commercially attractive markets to the pharmaceutical industry with current marketing paradigms. However, the ability to target patients more accurately may represent considerable commercial value within a given market sector. Changes in health care policy and structure will be needed so that short-term budget constraints are not allowed to take precedence over mid- to long-term benefits. In order to realize the potential of pharmacogenetics, tailored communication/education programs for the key stakeholders--patients and patient groups, health care professionals, regulators, health care industry (biotechnology, pharmaceutical and diagnostic companies), health care payers, governments, and academia--will be necessary

Pharmacokinetic and pharmacogenetic markers of irinotecan toxicity.

PubMed

Hahn, Roberta Zilles; Antunes, Marina Venzon; Verza, Simone Gasparin; Perassolo, Magda Susana; Suyenaga, Edna Sayuri; Schwartsmann, Gilberto; Linden, Rafael

2018-06-22

Irinotecan (IRI) is a widely used chemotherapeutic drug, mostly used for first-line treatment of colorectal and pancreatic cancer. IRI doses are usually established based on patient's body surface area, an approach associated with large inter-individual variability in drug exposure and high incidence of severe toxicity. Toxic and therapeutic effects of IRI are also due to its active metabolite SN-38, reported to be up to 100 times more cytotoxic than IRI. SN-38 is detoxified by the formation of SN-38 glucuronide, through UGT1A1. Genetic polymorphisms in the UGT1A1 gene are associated to higher exposures to SN-38 and severe toxicity. Pharmacokinetic models to describe IRI and SN-38 kinetic profiles are available, with few studies exploring pharmacokinetic and pharmacogenetic-based dose individualization. The aim of this manuscript is to review the available evidence supporting pharmacogenetic and pharmacokinetic dose individualization of IRI in order to reduce the occurrence of severe toxicity during cancer treatment. The PubMed database was searched, considering papers published in the period from 1995-2017, using the keywords irinotecan, pharmacogenetics, metabolic genotyping, dose individualization, therapeutic drug monitoring, pharmacokinetics and pharmacodynamics, either alone or in combination, with original papers being selected based on the presence of relevant data. The findings of this review confirm the importance of considering individual patient characteristics to select IRI doses. Currently, the most straightforward approach for IRI dose individualization is UGT1A1 genotyping. However, this strategy is sub-optimal due to several other genetic and environmental contributions to the variable pharmacokinetics of IRI and its active metabolite. The use of dried blood spot sampling could allow the clinical application of complex sampling for the clinical use of limited sampling and population pharmacokinetic models for IRI doses individualization. Copyright

Pharmacogenetics and Cardiovascular Disease—Implications for Personalized Medicine

PubMed Central

Cavallari, Larisa H.

2013-01-01

The past decade has seen tremendous advances in our understanding of the genetic factors influencing response to a variety of drugs, including those targeted at treatment of cardiovascular diseases. In the case of clopidogrel, warfarin, and statins, the literature has become sufficiently strong that guidelines are now available describing the use of genetic information to guide treatment with these therapies, and some health centers are using this information in the care of their patients. There are many challenges in moving from research data to translation to practice; we discuss some of these barriers and the approaches some health systems are taking to overcome them. The body of literature that has led to the clinical implementation of CYP2C19 genotyping for clopidogrel, VKORC1, CYP2C9; and CYP4F2 for warfarin; and SLCO1B1 for statins is comprehensively described. We also provide clarity for other genes that have been extensively studied relative to these drugs, but for which the data are conflicting. Finally, we comment briefly on pharmacogenetics of other cardiovascular drugs and highlight β-blockers as the drug class with strong data that has not yet seen clinical implementation. It is anticipated that genetic information will increasingly be available on patients, and it is important to identify those examples where the evidence is sufficiently robust and predictive to use genetic information to guide clinical decisions. The review herein provides several examples of the accumulation of evidence and eventual clinical translation in cardiovascular pharmacogenetics. PMID:23686351

Pharmacology and pharmacogenetics of chemotherapeutic agents.

PubMed

Dawood, Shaheenah; Leyland-Jones, Brian

2009-06-01

The last decade the field of oncology has seen the introduction of several efficacious chemotherapeutic agents. However the benefits achieved have been modest at best. The choice of chemotherapeutic agent is often empirical and geared to fit the average patient with the result that approximately 40% of patients may be receiving the wrong drug. With greater understanding of the mechanisms behind the heterogeneity observed across patient populations, both in terms of efficacy and toxicity of a variety of therapeutic agents, research has now focused on individualizing treatment strategies by incorporating a combination of physiological variables, genetic characteristics and environmental factors together with the traditional tumor characteristics that currently drives clinical decision making. This review focuses on defining some of the principle components of personalized medicine. In addition we will review the pharmacological and pharmacogenetic predictors of toxic effects of chemotherapeutic agents drawing on examples of commonly used agents in oncology.

A Novel Admixture-Based Pharmacogenetic Approach to Refine Warfarin Dosing in Caribbean Hispanics

PubMed Central

Claudio-Campos, Karla; Rivera-Miranda, Giselle; Bermúdez-Bosch, Luis; Renta, Jessicca Y.; Cadilla, Carmen L.; Cruz, Iadelisse; Feliu, Juan F.; Vergara, Cunegundo; Ruaño, Gualberto

2016-01-01

Aim This study is aimed at developing a novel admixture-adjusted pharmacogenomic approach to individually refine warfarin dosing in Caribbean Hispanic patients. Patients & Methods A multiple linear regression analysis of effective warfarin doses versus relevant genotypes, admixture, clinical and demographic factors was performed in 255 patients and further validated externally in another cohort of 55 individuals. Results The admixture-adjusted, genotype-guided warfarin dosing refinement algorithm developed in Caribbean Hispanics showed better predictability (R2 = 0.70, MAE = 0.72mg/day) than a clinical algorithm that excluded genotypes and admixture (R2 = 0.60, MAE = 0.99mg/day), and outperformed two prior pharmacogenetic algorithms in predicting effective dose in this population. For patients at the highest risk of adverse events, 45.5% of the dose predictions using the developed pharmacogenetic model resulted in ideal dose as compared with only 29% when using the clinical non-genetic algorithm (p<0.001). The admixture-driven pharmacogenetic algorithm predicted 58% of warfarin dose variance when externally validated in 55 individuals from an independent validation cohort (MAE = 0.89 mg/day, 24% mean bias). Conclusions Results supported our rationale to incorporate individual’s genotypes and unique admixture metrics into pharmacogenetic refinement models in order to increase predictability when expanding them to admixed populations like Caribbean Hispanics. Trial Registration ClinicalTrials.gov NCT01318057 PMID:26745506

A review of pharmacogenetic studies of substance-related disorders*

PubMed Central

Jones, Jermaine D.; Comer, Sandra D.

2015-01-01

Background Substance-related disorders (SRDs) are a major cause of morbidity and mortality worldwide. Family, twin, and adoption studies have demonstrated the substantial heritability of SRDs. To determine the impact of genetic variation on risk for SRD and the response to treatment, researchers have conducted a number of secondary data analyses and quasi-experimental studies that target one or more candidate gene variants. Methods This review examines studies in which candidate polymorphisms were examined as mediator variables to identify pharmacogenetic effects on subjective responses to drug administration or cues or outcomes of medication trials for SRDs. Efforts to use a meta-analytic approach to quantify these effects are premature because the number of available studies using similar methods and outcomes is limited, so the present review is qualitative. Results Findings from these studies provide preliminary evidence of clinically relevant pharmacogenetic effects. However, independent replication of these findings has been sparse. Conclusions Although this growing body of literature has produced conflicting results, improved statistical controls may help to clarify the findings. Additionally, the use of empirically derived sub-phenotypes (i.e., which serve to differentiate distinct groups of affected individuals) may also help to identify genetic mediators of pharmacologic response in relation to SRDs. The identification of genetic mediators can inform clinical care both by identifying risk factors for SRDs and predicting adverse events and therapeutic outcomes associated with specific pharmacotherapies. PMID:25819021

A review of pharmacogenetic studies of substance-related disorders.

PubMed

Jones, Jermaine D; Comer, Sandra D

2015-07-01

Substance-related disorders (SRDs) are a major cause of morbidity and mortality worldwide. Family, twin, and adoption studies have demonstrated the substantial heritability of SRDs. To determine the impact of genetic variation on risk for SRD and the response to treatment, researchers have conducted a number of secondary data analyses and quasi-experimental studies that target one or more candidate gene variants. This review examines studies in which candidate polymorphisms were examined as mediator variables to identify pharmacogenetic effects on subjective responses to drug administration or cues or outcomes of medication trials for SRDs. Efforts to use a meta-analytic approach to quantify these effects are premature because the number of available studies using similar methods and outcomes is limited, so the present review is qualitative. Findings from these studies provide preliminary evidence of clinically relevant pharmacogenetic effects. However, independent replication of these findings has been sparse. Although this growing body of literature has produced conflicting results, improved statistical controls may help to clarify the findings. Additionally, the use of empirically derived sub-phenotypes (i.e., which serve to differentiate distinct groups of affected individuals) may also help to identify genetic mediators of pharmacologic response in relation to SRDs. The identification of genetic mediators can inform clinical care both by identifying risk factors for SRDs and predicting adverse events and therapeutic outcomes associated with specific pharmacotherapies. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Pharmacogenetics in obstetric anesthesia.

PubMed

Landau, Ruth; Kraft, John C

2010-06-01

Genomic research in pain, anesthesia and analgesia generated some hope that pharmacogenetics may guide anesthesiologists to provide effective medicine in a 'tailored' manner. Within the field of obstetric anesthesia, relatively few studies have evaluated the effect of polymorphisms on the perception of labor or postcesarean pain or the response to analgesics for childbirth. Because of the multifactorial nature of labor and delivery pain and particularly challenging clinical context, many consider that 'titration of drugs to the desired effect works just fine'. With recent evidence highlighting an association between severe postdelivery pain and persistent pain, early recognition of an increased susceptibility for acute pain has become particularly relevant. Neuraxial labor analgesia is influenced by a common polymorphism of the mu-opioid receptor gene. This polymorphism also affects the analgesic response to systemic opioids for postcesarean pain and other types of surgeries. Finally, the risk for persistent pain after cesarean deliveries may be associated with a certain genetic profile. Although still premature to anticipate clinical implications and a change in practice based on these recent discoveries, genetic variability clearly appears to affect pain perception, response to analgesics and predisposition for the development of chronic pain.

Cost-effectiveness of pharmacogenetics-guided warfarin therapy vs. alternative anticoagulation in atrial fibrillation.

PubMed

Pink, J; Pirmohamed, M; Lane, S; Hughes, D A

2014-02-01

Pharmacogenetics-guided warfarin dosing is an alternative to standard clinical algorithms and new oral anticoagulants for patients with nonvalvular atrial fibrillation. However, clinical evidence for pharmacogenetics-guided warfarin dosing is limited to intermediary outcomes, and consequently, there is a lack of information on the cost-effectiveness of anticoagulation treatment options. A clinical trial simulation of S-warfarin was used to predict times within therapeutic range for different dosing algorithms. Relative risks of clinical events, obtained from a meta-analysis of trials linking times within therapeutic range with outcomes, served as inputs to an economic analysis. Neither dabigatran nor rivaroxaban were cost-effective options. Along the cost-effectiveness frontier, in relation to clinically dosed warfarin, pharmacogenetics-guided warfarin and apixaban had incremental cost-effectiveness ratios of £13,226 and £20,671 per quality-adjusted life year gained, respectively. On the basis of our simulations, apixaban appears to be the most cost-effective treatment.

Pharmacogenetics and pharmacogenomics in drug development and regulatory decision making: report of the first FDA-PWG-PhRMA-DruSafe Workshop.

PubMed

Lesko, Lawrence J; Salerno, Ronald A; Spear, Brian B; Anderson, Donald C; Anderson, Timothy; Brazell, Celia; Collins, Jerry; Dorner, Andrew; Essayan, David; Gomez-Mancilla, Baltazar; Hackett, Joseph; Huang, Shiew-Mei; Ide, Susan; Killinger, Joanne; Leighton, John; Mansfield, Elizabeth; Meyer, Robert; Ryan, Stephen G; Schmith, Virginia; Shaw, Peter; Sistare, Frank; Watson, Mark; Worobec, Alexandra

2003-04-01

The use of pharmacogenetics and pharmacogenomics in the drug development process, and in the assessment of such data submitted to regulatory agencies by industry, has generated significant enthusiasm as well as important reservations within the scientific and medical communities. This situation has arisen because of the increasing number of exploratory and confirmatory investigations into variations in RNA expression patterns and DNA sequences being conducted in the preclinical and clinical phases of drug development, and the uncertainty surrounding the acceptance of these data by regulatory agencies. This report summarizes the outcome of a workshop cosponsored by the Food and Drug Administration (FDA), the Pharmacogenetics Working Group (PWG), the Pharmaceutical Research and Manufacturers of America (PhRMA), and the PhRMA Preclinical Safety Committee (DruSafe). The specific aim of the workshop was to identify key issues associated with the application of pharmacogenetics and pharmacogenomics, including the feasibility of a regulatory "safe harbor" for exploratory genome-based data, and to provide a forum for industry-regulatory agency dialogue on these important issues.

Pharmacogenetics of the Neurodevelopmental Impact of Anticancer Chemotherapy

ERIC Educational Resources Information Center

Robaey, Philippe; Krajinovic, Maja; Marcoux, Sophie; Moghrabi, Albert

2008-01-01

Pharmacogenetics holds the promise of minimizing adverse neurodevelopmental outcomes of cancer patients by identifying patients at risk, enabling the individualization of treatment and the planning of close follow-up and early remediation. This review focuses first on methotrexate, a drug often implicated in neurotoxicity, especially when used in…

Analysis of pharmacogenetic traits in two distinct South African populations

PubMed Central

2011-01-01

Our knowledge of pharmacogenetic variability in diverse populations is scarce, especially in sub-Saharan Africa. To bridge this gap in knowledge, we characterised population frequencies of clinically relevant pharmacogenetic traits in two distinct South African population groups. We genotyped 211 tagging single nucleotide polymorphisms (tagSNPs) in 12 genes that influence antiretroviral drug disposition, in 176 South African individuals belonging to two distinct population groups residing in the Western Cape: the Xhosa (n = 109) and Cape Mixed Ancestry (CMA) (n = 67) groups. The minor allele frequencies (MAFs) of eight tagSNPs in six genes (those encoding the ATP binding cassette sub-family B, member 1 [ABCB1], four members of the cytochrome P450 family [CYP2A7P1, CYP2C18, CYP3A4, CYP3A5] and UDP-glucuronosyltransferase 1 [UGT1A1]) were significantly different between the Xhosa and CMA populations (Bonferroni p < 0.05). Twenty-seven haplotypes were inferred in four genes (CYP2C18, CYP3A4, the gene encoding solute carrier family 22 member 6 [SLC22A6] and UGT1A1) between the two South African populations. Characterising the Xhosa and CMA population frequencies of variant alleles important for drug transport and metabolism can help to establish the clinical relevance of pharmacogenetic testing in these populations. PMID:21712189

Pharmacogenetics and forensic toxicology.

PubMed

Musshoff, Frank; Stamer, Ulrike M; Madea, Burkhard

2010-12-15

Large inter-individual variability in drug response and toxicity, as well as in drug concentrations after application of the same dosage, can be of genetic, physiological, pathophysiological, or environmental origin. Absorption, distribution and metabolism of a drug and interactions with its target often are determined by genetic differences. Pharmacokinetic and pharmacodynamic variations can appear at the level of drug metabolizing enzymes (e.g., the cytochrome P450 system), drug transporters, drug targets or other biomarker genes. Pharmacogenetics or toxicogenetics can therefore be relevant in forensic toxicology. This review presents relevant aspects together with some examples from daily routines. Copyright © 2010. Published by Elsevier Ireland Ltd.

Pharmacogenetic tests: the need for a level playing field.

PubMed

Pirmohamed, Munir; Hughes, Dyfrig A

2013-01-01

The delivery of more personalized medicinecould be accelerated by addressing the substantial differences in the level of evidence required for the inclusion of pharmacogenetic tests in treatment guidelines, drug labelling and reimbursement schemes compared with that needed for non-genetic diagnostic tests.

A Systematic Review of Economic Evaluations of Pharmacogenetic Testing for Prevention of Adverse Drug Reactions.

PubMed

Plumpton, Catrin O; Roberts, Daniel; Pirmohamed, Munir; Hughes, Dyfrig A

2016-08-01

Pharmacogenetics offers the potential to improve health outcomes by identifying individuals who are at greater risk of harm from certain medicines. Routine adoption of pharmacogenetic tests requires evidence of their cost effectiveness. The present review aims to systematically review published economic evaluations of pharmacogenetic tests that aim to prevent or reduce the incidence of ADRs. We conducted a systematic literature review of economic evaluations of pharmacogenetic tests aimed to reduce the incidence of adverse drug reactions. Literature was searched using Embase, MEDLINE and the NHS Economic Evaluation Database with search terms relating to pharmacogenetic testing, adverse drug reactions, economic evaluations and pharmaceuticals. Titles were screened independently by two reviewers. Articles deemed to meet the inclusion criteria were screened independently on abstract, and full texts reviewed. We identified 852 articles, of which 47 met the inclusion criteria. There was evidence supporting the cost effectiveness of testing for HLA-B*57:01 (prior to abacavir), HLA-B*15:02 and HLA-A*31:01 (prior to carbamazepine), HLA-B*58:01 (prior to allopurinol) and CYP2C19 (prior to clopidogrel treatment). Economic evidence was inconclusive with respect to TPMT (prior to 6-mercaptoputine, azathioprine and cisplatin therapy), CYP2C9 and VKORC1 (to inform genotype-guided dosing of coumarin derivatives), MTHFR (prior to methotrexate treatment) and factor V Leiden testing (prior to oral contraception). Testing for A1555G is not cost effective before prescribing aminoglycosides. Our systematic review identified robust evidence of the cost effectiveness of genotyping prior to treatment with a number of common drugs. However, further analyses and (or) availability of robust clinical evidence is necessary to make recommendations for others.

Impact of Pharmacogenetics on Efficacy and Safety of Statin Therapy for Dyslipidemia.

PubMed

Maxwell, Whitney D; Ramsey, Laura B; Johnson, Samuel G; Moore, Kate G; Shtutman, Michael; Schoonover, John H; Kawaguchi-Suzuki, Marina

2017-09-01

Interindividual variability in response to 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, or statins, with regard to both efficacy and safety is an obvious target for pharmacogenetic research. Many genes have been identified as possible contributors to variability in statin response and safety. Genetic polymorphisms may alter the structure or expression of coded proteins, with potential impacts on lipid and statin absorption, distribution, metabolism, and elimination as well as response pathways related to the pharmacologic effect. Many studies have explored the variation in statins' pharmacokinetic and pharmacodynamic parameters; however, to our knowledge, few have established definitive relationships between the genetic polymorphisms and patient outcomes, such as cardiovascular events. In this review article, we provide a statin-based summary of available evidence describing pharmacogenetic associations that may be of clinical relevance in the future. Although currently available studies are often small or retrospective, and may have conflicting results, they may be useful in providing direction for future confirmatory studies and may point to associations that could be confirmed in the future when more patient outcomes-based studies are available. We also summarize the clinically relevant evidence currently available to assist clinicians with providing personalized pharmacotherapy for patients requiring statin therapy. © 2017 Pharmacotherapy Publications, Inc.

Abacavir pharmacogenetics--from initial reports to standard of care.

PubMed

Martin, Michael A; Kroetz, Deanna L

2013-07-01

Abacavir is a nucleoside analogue reverse transcriptase inhibitor indicated for the treatment of human immunodeficiency virus infection as part of a multidrug, highly active antiretroviral therapy regimen. Despite its efficacy, approximately 5% of individuals who receive abacavir develop an immune-mediated hypersensitivity reaction (HSR) that warrants immediate discontinuation of abacavir and switching to an alternative antiretroviral regimen. Abacavir HSR is associated with individuals who carry the *57:01 variant in the human leukocyte antigen B (HLA-B) gene. There is a large volume of evidence to show that those who carry HLA-B*57:01 are at significantly increased risk of developing HSR and should not receive abacavir. Pharmacogenetic screening to ensure individuals who carry HLA-B*57:01 do not receive abacavir can reduce the incidence of HSR and is now considered the standard of care before prescribing abacavir. Genetic testing to prevent abacavir HSR is currently one of the best examples of integrating pharmacogenetic testing into clinical practice. © 2013 Pharmacotherapy Publications, Inc.

Challenges to Integrating Pharmacogenetic Testing into Medication Therapy Management

PubMed Central

Allen LaPointe, Nancy M.; Moaddeb, Jivan

2015-01-01

Background Some have proposed the integration of pharmacogenetic (PGx) testing into medication therapy management (MTM) to enable further refinement of treatment(s) to reduce risk of adverse responses and improve efficacy. PGx testing involves the analysis of genetic variants associated with therapeutic or adverse response and may be useful in enhancing the ability to identify ineffective and/or harmful drugs or drug combinations. This “enhanced” MTM might also reduce patient concerns about side effects and increase confidence that the medication is effective, addressing two key factors that impact patient adherence - concern and necessity. However, the feasibility and effectiveness of the integration of PGx testing into MTM in clinical practice has not yet been determined. Objectives In this paper, we consider some of the challenges to the integration and delivery of PGx testing in MTM services. What is already known about this subject While the addition of pharmacogenetic testing has been suggested, little literature exists exploring the challenges or feasibility of doing so. PMID:25803768

Individual variability in clinical effect and tolerability of opioid analgesics - Importance of drug interactions and pharmacogenetics.

PubMed

Solhaug, Vigdis; Molden, Espen

2017-10-01

As pain is often a comorbid condition, many patients use opioid analgesics in combination with several other drugs. This implies a generally increased risk of drug interactions, which along with inherent pharmacogenetic variability and other factors may cause differences in therapeutic response of opioids. To provide an overview of interactions and pharmacogenetic variability of relevance for individual differences in effect and tolerability of opioid analgesics, which physicians and other healthcare professionals should be aware of in clinical practice. The article was based on unsystematic searches in PubMed to identify literature highlighting the clinical impact of drug interactions and pharmacogenetics as sources of variable response of opioid analgesics. Cytochrome P450 (CYP)-mediated metabolism is an important process for both clinically relevant interactions and pharmacogenetic variability of several opioids. Concomitant use of CYP inhibitors (e.g. paroxetine, fluoxetine and bupropion) or inducers (e.g. carbamazepine, phenobarbital and phenytoin) could counteract the clinical effect or trigger side effects of analgesics in the same manner as genetically determined differences in CYP2D6-mediated metabolism of many opioids. Moreover, combination treatment with drugs that inhibit or induce P-glycoprotein (ABCB1), a blood-brain barrier efflux transporter, may alter the amount ('dose') of opioids distributed to the brain. At the pharmacodynamic level, it is crucial to be aware of the potential risk of interaction causing serotonergic syndrome when combining opioids and serotonergic drugs, in particular antidepressants inhibiting serotonin reuptake (SSRIs and SNRIs). Regarding pharmacogenetics at the receptor level of pain treatment, the knowledge is currently scarce, but an allelic variant of the μ1 opioid receptor (OPRM1) gene has been associated with higher dosage requirement to achieve analgesia. Drug interactions and pharmacogenetic differences may lead to

Pharmacogenetics research on chemotherapy resistance in colorectal cancer over the last 20 years

PubMed Central

Panczyk, Mariusz

2014-01-01

During the past two decades the first sequencing of the human genome was performed showing its high degree of inter-individual differentiation, as a result of large international research projects (Human Genome Project, the 1000 Genomes Project International HapMap Project, and Programs for Genomic Applications NHLBI-PGA). This period was also a time of intensive development of molecular biology techniques and enormous knowledge growth in the biology of cancer. For clinical use in the treatment of patients with colorectal cancer (CRC), in addition to fluoropyrimidines, another two new cytostatic drugs were allowed: irinotecan and oxaliplatin. Intensive research into new treatment regimens and a new generation of drugs used in targeted therapy has also been conducted. The last 20 years was a time of numerous in vitro and in vivo studies on the molecular basis of drug resistance. One of the most important factors limiting the effectiveness of chemotherapy is the primary and secondary resistance of cancer cells. Understanding the genetic factors and mechanisms that contribute to the lack of or low sensitivity of tumour tissue to cytostatics is a key element in the currently developing trend of personalized medicine. Scientists hope to increase the percentage of positive treatment response in CRC patients due to practical applications of pharmacogenetics/pharmacogenomics. Over the past 20 years the clinical usability of different predictive markers has been tested among which only a few have been confirmed to have high application potential. This review is a synthetic presentation of drug resistance in the context of CRC patient chemotherapy. The multifactorial nature and volume of the issues involved do not allow the author to present a comprehensive study on this subject in one review. PMID:25110414

Data science approaches to pharmacogenetics.

PubMed

Penrod, N M; Moore, J H

2014-01-01

Pharmacogenetic studies rely on applied statistics to evaluate genetic data describing natural variation in response to pharmacotherapeutics such as drugs and vaccines. In the beginning, these studies were based on candidate gene approaches that specifically focused on efficacy or adverse events correlated with variants of single genes. This hypothesis driven method required the researcher to have a priori knowledge of which genes or gene sets to investigate. According to rational design, the focus of these studies has been on drug metabolizing enzymes, drug transporters, and drug targets. As technology has progressed, these studies have transitioned to hypothesis-free explorations where markers across the entire genome can be measured in large scale, population based, genome-wide association studies (GWAS). This enables identification of novel genetic biomarkers, therapeutic targets, and analysis of gene-gene interactions, which may reveal molecular mechanisms of drug activities. Ultimately, the challenge is to utilize gene-drug associations to create dosing algorithms based individual genotypes, which will guide physicians and ensure they prescribe the correct dose of the correct drug the first time eliminating trial-and-error and adverse events. We review here basic concepts and applications of data science to the genetic analysis of pharmacologic outcomes.

Pharmacogenetic considerations for optimizing tacrolimus dosing in liver and kidney transplant patients

PubMed Central

Provenzani, Alessio; Santeusanio, Andrew; Mathis, Erin; Notarbartolo, Monica; Labbozzetta, Manuela; Poma, Paola; Provenzani, Ambra; Polidori, Carlo; Vizzini, Giovanni; Polidori, Piera; D’Alessandro, Natale

2013-01-01

The introduction of tacrolimus in clinical practice has improved patient survival after organ transplant. However, despite the long use of tacrolimus in clinical practice, the best way to use this agent is still a matter of intense debate. The start of the genomic era has generated new research areas, such as pharmacogenetics, which studies the variability of drug response in relation to the genetic factors involved in the processes responsible for the pharmacokinetics and/or the action mechanism of a drug in the body. This variability seems to be correlated with the presence of genetic polymorphisms. Genotyping is an attractive option especially for the initiation of the dosing of tacrolimus; also, unlike phenotypic tests, the genotype is a stable characteristic that needs to be determined only once for any given gene. However, prospective clinical studies must show that genotype determination before transplantation allows for better use of a given drug and improves the safety and clinical efficacy of that medication. At present, research has been able to reliably show that the CYP3A5 genotype, but not the CYP3A4 or ABCB1 ones, can modify the pharmacokinetics of tacrolimus. However, it has not been possible to incontrovertibly show that the corresponding changes in the pharmacokinetic profile are linked with different patient outcomes regarding tacrolimus efficacy and toxicity. For these reasons, pharmacogenetics and individualized medicine remain a fascinating area for further study and may ultimately become the face of future medical practice and drug dosing. PMID:24409044

Individualized Hydrocodone Therapy Based on Phenotype, Pharmacogenetics, and Pharmacokinetic Dosing.

PubMed

Linares, Oscar A; Fudin, Jeffrey; Daly, Annemarie L; Boston, Raymond C

2015-12-01

(1) To quantify hydrocodone (HC) and hydromorphone (HM) metabolite pharmacokinetics with pharmacogenetics in CYP2D6 ultra-rapid metabolizer (UM), extensive metabolizer (EM), and poor metabolizer (PM) metabolizer phenotypes. (2) To develop an HC phenotype-specific dosing strategy for HC that accounts for HM production using clinical pharmacokinetics integrated with pharmacogenetics for patient safety. In silico clinical trial simulation. Healthy white men and women without comorbidities or history of opioid, or any other drug or nutraceutical use, age 26.3±5.7 years (mean±SD; range, 19 to 36 y) and weight 71.9±16.8 kg (range, 50 to 108 kg). CYP2D6 phenotype-specific HC clinical pharmacokinetic parameter estimates and phenotype-specific percentages of HM formed from HC. PMs had lower indices of HC disposition compared with UMs and EMs. Clearance was reduced by nearly 60% and the t1/2 was increased by about 68% compared with EMs. The canonical order for HC clearance was UM>EM>PM. HC elimination mainly by the liver, represented by ke, was reduced about 70% in PM. However, HC's apparent Vd was not significantly different among UMs, EMs, and PM. The canonical order of predicted plasma HM concentrations was UM>EM>PM. For each of the CYP2D6 phenotypes, the mean predicted HM levels were within HM's therapeutic range, which indicates HC has significant phenotype-dependent pro-drug effects. Our results demonstrate that pharmacogenetics afford clinicians an opportunity to individualize HC dosing, while adding enhanced opportunity to account for its conversion to HM in the body.

Characterization of 137 Genomic DNA Reference Materials for 28 Pharmacogenetic Genes: A GeT-RM Collaborative Project.

PubMed

Pratt, Victoria M; Everts, Robin E; Aggarwal, Praful; Beyer, Brittany N; Broeckel, Ulrich; Epstein-Baak, Ruth; Hujsak, Paul; Kornreich, Ruth; Liao, Jun; Lorier, Rachel; Scott, Stuart A; Smith, Chingying Huang; Toji, Lorraine H; Turner, Amy; Kalman, Lisa V

2016-01-01

Pharmacogenetic testing is increasingly available from clinical laboratories. However, only a limited number of quality control and other reference materials are currently available to support clinical testing. To address this need, the Centers for Disease Control and Prevention-based Genetic Testing Reference Material Coordination Program, in collaboration with members of the pharmacogenetic testing community and the Coriell Cell Repositories, has characterized 137 genomic DNA samples for 28 genes commonly genotyped by pharmacogenetic testing assays (CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4, CYP3A5, CYP4F2, DPYD, GSTM1, GSTP1, GSTT1, NAT1, NAT2, SLC15A2, SLC22A2, SLCO1B1, SLCO2B1, TPMT, UGT1A1, UGT2B7, UGT2B15, UGT2B17, and VKORC1). One hundred thirty-seven Coriell cell lines were selected based on ethnic diversity and partial genotype characterization from earlier testing. DNA samples were coded and distributed to volunteer testing laboratories for targeted genotyping using a number of commercially available and laboratory developed tests. Through consensus verification, we confirmed the presence of at least 108 variant pharmacogenetic alleles. These samples are also being characterized by other pharmacogenetic assays, including next-generation sequencing, which will be reported separately. Genotyping results were consistent among laboratories, with most differences in allele assignments attributed to assay design and variability in reported allele nomenclature, particularly for CYP2D6, UGT1A1, and VKORC1. These publicly available samples will help ensure the accuracy of pharmacogenetic testing. Copyright © 2016 American Society for Investigative Pathology and the Association for Molecular Pathology. Published by Elsevier Inc. All rights reserved.

Routine pharmacogenetic testing in clinical practice: dream or reality?

PubMed

Grossman, Iris

2007-10-01

Pharmacogenetics (PGx) has become progressively popular in recent years, thanks to growing anticipation among scientists, healthcare providers and the general public for the incorporation of genetic tests into the diagnostic arsenal at the physician's disposal. Indeed, much research has been dedicated to elucidation of genetic determinants underlying interindividual variability in pharmacokinetic parameters, as well as drug safety and efficacy. However, few PGx applications have thus far been realized in healthcare management. This review uses examples from PGx research of psychiatric drugs to illustrate why the current published findings are inadequate and insufficient for utilization as routine clinical predictors of treatment safety, efficacy or dosing. I therefore suggest the necessary steps to demonstrate the validity, utility and cost-effectiveness of PGx. These recommendations include a whole range of aspects, starting from standardization of criteria and assessment of the technical quality of genotyping assays, up to design of prospective PGx studies, providing the basis for reimbursement programs to be recognized in routine clinical practice.

Novel Use of Pharmacogenetic Testing in the Identification of CYP2C9 Polymorphisms Related to NSAID-Induced Gastropathy.

PubMed

Gupta, Anita; Zheng, Lu; Ramanujam, Vendhan; Gallagher, John

2015-05-01

To illustrate the potential value of pharmacogenetic testing to identify patients at risk for nonsteroidal anti-inflammatory drug-induced gastropathy. Case report. We report a case encountered in an outpatient setting for pain management. We present a case of a patient treated with celecoxib who developed severe nonsteroidal anti-inflammatory drug-induced gastropathy. Suspecting a relation between this adverse event and altered drug metabolism, pharmacogenetic testing was performed to assess the role of the cytochrome P450 (CP450) enzyme profile. Pharmacogenetic testing revealed a relation between this adverse event and an allelic variant of cytochrome P450, CYP2C9, subsequently leading to discontinuation of the drug along with counseling to caution the patient to avoid the use of celecoxib and other drugs metabolized by the same enzyme. Although pharmacogenetic testing is not routinely used in clinical decision making, pain physicians must be aware of the potential benefits of this testing for managing patients with pain, and to improve drug efficacy and safety profile. Wiley Periodicals, Inc.

Estrogen-Mediated Breast Carcinogenesis: The Role of Sulfation Pharmacogenetics

DTIC Science & Technology

2000-05-01

DATE 3. REPORT TYPE AND DATES COVERED IMay 2000 Annual (1 May 99 - 30 Apr 00) 4. TITLE AND SUBTITLE 5 . FUNDING NUMBERS Estrogen-Mediated Breast...Carcinogenesis: The Role of DAMD17-99-1-9281 Sulfation Pharmacogenetics 6 . AUTHOR(S) Araba Adjei, Ph.D. 7. PERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES... 5 B O D Y

Pharmacogenetics in cancer therapy - 8 years of experience at the Institute for Oncology and Radiology of Serbia.

PubMed

Cavic, Milena; Krivokuca, Ana; Boljevic, Ivana; Brotto, Ksenija; Jovanovic, Katarina; Tanic, Miljana; Filipovic, Lana; Zec, Manja; Malisic, Emina; Jankovic, Radmila; Radulovic, Sinisa

2016-01-01

Pharmacogenetics is a study of possible mechanism by which an individual's response to drugs is genetically determined by variations in their DNA sequence. The aim of pharmacogenetics is to identify the optimal drug and dose for each individual based on their genetic constitution, i.e. to individualize drug treatment. This leads to achieving the maximal therapeutic response for each patient, while reducing adverse side effects of therapy and the cost of treatment. A centralized pharmacogenetics service was formed at the Institute for Oncology and Radiology of Serbia (IORS) with the aim to provide a personalized approach to cancer treatment of Serbian patients. Analyses of KRAS mutations in metastatic colorectal cancer, EGFR mutations in advanced non-small cell lung cancer, CYP2D6 polymorphism in breast cancer, DPD polymorphism in colorectal cancer and MTHFR polymorphism in osteosarcoma have been performed by real time polymerase chain reaction (PCR) and PCR-restriction fragment length polymorphism (PCR-RFLP). Mutation testing analyses were successful for 1694 KRAS samples and 1821 EGFR samples, while polymorphism testing was successful for 9 CYP2D6 samples, 65 DPD samples and 35 MTHFR samples. Pharmacogenetic methods presented in this paper provide cancer patients in Serbia the best possible choice of treatment at the moment.

The future of pharmacogenetics in the treatment of heart failure.

PubMed

Anwar, Mohamed Subhan; Iskandar, Muhammad Zaid; Parry, Helen M; Doney, Alex S; Palmer, Colin N; Lang, Chim C

2015-11-01

Heart failure is a common disease with high levels of morbidity and mortality. Current treatment comprises β-blockers, ACE inhibitors, aldosterone antagonists and diuretics. Variation in clinical response seen in patients begs the question of whether there is a pharmacogenetic component yet to be identified. To date, the genes most studied involve the β-1, β-2, α-2 adrenergic receptors and the renin-angiotensin-aldosterone pathway, mainly focusing on SNPs. However results have been inconsistent. Genome-wide association studies and next-generation sequencing are seen as alternative approaches to discovering genetic variations influencing drug response. Hopefully future research will lay the foundations for genotype-led drug management in these patients with the ultimate aim of improving their clinical outcome.

Clinical application of antidepressant pharmacogenetics: considerations for the design of future studies.

PubMed

Fabbri, Chiara; Serretti, Alessandro

2018-06-12

A frustrating inertia has affected the development of clinical applications of antidepressant pharmacogenetics and personalized treatments of depression are still lacking 20 years after the first findings. Candidate gene studies provided replicated findings for some polymorphisms, but each of them shows at best a small effect on antidepressant efficacy and the cumulative effect of different polymorphisms is unclear. Further, no candidate was immune by at least some negative studies. These considerations give rise to some concerns about the clinical benefits of currently available pharmacogenetic tests since they are based on the results of candidate gene studies. Clinical guidelines in fact suggest that only polymorphisms that alter cytochrome 2D6 or 2C19 enzymatic activity probably provide useful clinical indications, while variants in genes involved in antidepressant pharmacodynamics have no recommended clinical applications. The present review discusses possible strategies to facilitate the identification of genetic biomarkers with clinical usefulness in guiding antidepressant treatments. These include analysis methods for the study of the polygenic/omnigenic nature of antidepressant response, the prioritization of polymorphisms on the basis of functional considerations, the incorporation of clinical-demographic predictors in pharmacogenetic studies (e.g. mixed polygenic and clinical risk scores), the application of methodological improvements to the design of future studies in order to maximize the comparability of results and improve power. Copyright © 2018. Published by Elsevier B.V.

Pharmacogenetic evaluation to assess breakthrough psychosis with aripiprazole long-acting injection: a case report.

PubMed

Eum, Seenae; Schneiderhan, Mark E; Brown, Jacob T; Lee, Adam M; Bishop, Jeffrey R

2017-07-03

Given the complex nature of symptom presentation and medication regimens, psychiatric clinics may benefit from additional tools to personalize treatments. Utilizing pharmacogenetic information may be helpful in assessing unique responses to therapy. We report herein a case of wearing-off phenomena during treatment with aripiprazole long-acting injectable (LAI) and a proof of concept strategy of how pharmacogenetic information may be used to assess possible genetic factors and also hypothesize potential mechanisms for further study. A 51-year-old African American male with schizoaffective disorder was referred to a psychiatric clinic for medication management. After unsuccessful trials of multiple antipsychotics, oral aripiprazole was initiated (up to 30 mg/day) and transitioned to aripiprazole LAI with symptom improvement. At a high dose of aripiprazole LAI (400 mg Q3wks), the patient experienced breakthrough symptoms approximately 3 days prior to his next injection. Various considerations were examined to explain his atypical dose requirements, including but not limited to pharmacogenetic influences. Pharmacogenetic testing ruled out genetic influences on drug metabolism but noted a -141C Del variant in the dopamine-D2 receptor (DRD2) gene associated in prior studies of poor-response to antipsychotics. At this time, a new formulation, aripiprazole lauroxil, was explored due to its availability in higher dose options. Transition to the new formulation (882 mg Q4wks) greatly improved and stabilized the patient's symptoms with no breakthrough psychosis. Comparable daily dose equivalents were achieved with two different formulations due to the Q3wks vs Q4wks dosing strategies, although the two agents have some differences in pharmacokinetic profiles. We report a case of a patient experiencing wearing-off symptoms with aripiprazole LAI who benefited from switching to aripiprazole lauroxil. Pharmacogenetic testing revealed normal activity for relevant metabolism

Pharmacogenetics in type 2 diabetes: influence on response to oral hypoglycemic agents

PubMed Central

Dawed, Adem Yesuf; Zhou, Kaixin; Pearson, Ewan Robert

2016-01-01

Type 2 diabetes is one of the leading causes of morbidity and mortality, consuming a significant proportion of public health spending. Oral hypoglycemic agents (OHAs) are the frontline treatment approaches after lifestyle changes. However, huge interindividual variation in response to OHAs results in unnecessary treatment failure. In addition to nongenetic factors, genetic factors are thought to contribute to much of such variability, highlighting the importance of the potential of pharmacogenetics to improve therapeutic outcome. Despite the presence of conflicting results, significant progress has been made in an effort to identify the genetic markers associated with pharmacokinetics, pharmacodynamics, and ultimately therapeutic response and/or adverse outcomes to OHAs. As such, this article presents a comprehensive review of current knowledge on pharmacogenetics of OHAs and provides insights into knowledge gaps and future directions. PMID:27103840

Review of Opioid Pharmacogenetics and Considerations for Pain Management.

PubMed

Owusu Obeng, Aniwaa; Hamadeh, Issam; Smith, Michael

2017-09-01

Opioid analgesics are the standards of care for the treatment of moderate to severe nociceptive pain, particularly in the setting of cancer and surgery. Their analgesic properties mainly emanate from stimulation of the μ receptors, which are encoded by the OPRM1 gene. Hepatic metabolism represents the major route of elimination, which, for some opioids, namely codeine and tramadol, is necessary for their bioactivation into more potent analgesics. The highly polymorphic nature of the genes coding for phase I and phase II enzymes (pharmacokinetics genes) that are involved in the metabolism and bioactivation of opioids suggests a potential interindividual variation in their disposition and, most likely, response. In fact, such an association has been substantiated in several pharmacokinetic studies described in this review, in which drug exposure and/or metabolism differed significantly based on the presence of polymorphisms in these pharmacokinetics genes. Furthermore, in some studies, the observed variability in drug exposure translated into differences in the incidence of opioid-related adverse effects, particularly nausea, vomiting, constipation, and respiratory depression. Although the influence of polymorphisms in pharmacokinetics genes, as well as pharmacodynamics genes (OPRM1 and COMT) on response to opioids has been a subject of intense research, the results have been somehow conflicting, with some evidence insinuating for a potential role for OPRM1. The Clinical Pharmacogenetics Implementation Consortium guidelines provide CYP2D6-guided therapeutic recommendations to individualize treatment with tramadol and codeine. However, implementation guidelines for other opioids, which are more commonly used in real-world settings for pain management, are currently lacking. Hence, further studies are warranted to bridge this gap in our knowledge base and ultimately ascertain the role of pharmacogenetic markers as predictors of response to opioid analgesics. © 2017

Pharmacogenetic meta-analysis of genome-wide association studies of LDL cholesterol response to statins

PubMed Central

Postmus, Iris; Trompet, Stella; Deshmukh, Harshal A.; Barnes, Michael R.; Li, Xiaohui; Warren, Helen R.; Chasman, Daniel I.; Zhou, Kaixin; Arsenault, Benoit J.; Donnelly, Louise A.; Wiggins, Kerri L.; Avery, Christy L.; Griffin, Paula; Feng, QiPing; Taylor, Kent D.; Li, Guo; Evans, Daniel S.; Smith, Albert V.; de Keyser, Catherine E.; Johnson, Andrew D.; de Craen, Anton J. M.; Stott, David J.; Buckley, Brendan M.; Ford, Ian; Westendorp, Rudi G. J.; Eline Slagboom, P.; Sattar, Naveed; Munroe, Patricia B.; Sever, Peter; Poulter, Neil; Stanton, Alice; Shields, Denis C.; O’Brien, Eoin; Shaw-Hawkins, Sue; Ida Chen, Y.-D.; Nickerson, Deborah A.; Smith, Joshua D.; Pierre Dubé, Marie; Matthijs Boekholdt, S.; Kees Hovingh, G.; Kastelein, John J. P.; McKeigue, Paul M.; Betteridge, John; Neil, Andrew; Durrington, Paul N.; Doney, Alex; Carr, Fiona; Morris, Andrew; McCarthy, Mark I.; Groop, Leif; Ahlqvist, Emma; Bis, Joshua C.; Rice, Kenneth; Smith, Nicholas L.; Lumley, Thomas; Whitsel, Eric A.; Stürmer, Til; Boerwinkle, Eric; Ngwa, Julius S.; O’Donnell, Christopher J.; Vasan, Ramachandran S.; Wei, Wei-Qi; Wilke, Russell A.; Liu, Ching-Ti; Sun, Fangui; Guo, Xiuqing; Heckbert, Susan R; Post, Wendy; Sotoodehnia, Nona; Arnold, Alice M.; Stafford, Jeanette M.; Ding, Jingzhong; Herrington, David M.; Kritchevsky, Stephen B.; Eiriksdottir, Gudny; Launer, Leonore J.; Harris, Tamara B.; Chu, Audrey Y.; Giulianini, Franco; MacFadyen, Jean G.; Barratt, Bryan J.; Nyberg, Fredrik; Stricker, Bruno H.; Uitterlinden, André G.; Hofman, Albert; Rivadeneira, Fernando; Emilsson, Valur; Franco, Oscar H.; Ridker, Paul M.; Gudnason, Vilmundur; Liu, Yongmei; Denny, Joshua C.; Ballantyne, Christie M.; Rotter, Jerome I.; Adrienne Cupples, L.; Psaty, Bruce M.; Palmer, Colin N. A.; Tardif, Jean-Claude; Colhoun, Helen M.; Hitman, Graham; Krauss, Ronald M.; Wouter Jukema, J; Caulfield, Mark J.; Donnelly, Peter; Barroso, Ines; Blackwell, Jenefer M.; Bramon, Elvira; Brown, Matthew A.; Casas, Juan P.; Corvin, Aiden; Deloukas, Panos; Duncanson, Audrey; Jankowski, Janusz; Markus, Hugh S.; Mathew, Christopher G.; Palmer, Colin N. A.; Plomin, Robert; Rautanen, Anna; Sawcer, Stephen J.; Trembath, Richard C.; Viswanathan, Ananth C.; Wood, Nicholas W.; Spencer, Chris C. A.; Band, Gavin; Bellenguez, Céline; Freeman, Colin; Hellenthal, Garrett; Giannoulatou, Eleni; Pirinen, Matti; Pearson, Richard; Strange, Amy; Su, Zhan; Vukcevic, Damjan; Donnelly, Peter; Langford, Cordelia; Hunt, Sarah E.; Edkins, Sarah; Gwilliam, Rhian; Blackburn, Hannah; Bumpstead, Suzannah J.; Dronov, Serge; Gillman, Matthew; Gray, Emma; Hammond, Naomi; Jayakumar, Alagurevathi; McCann, Owen T.; Liddle, Jennifer; Potter, Simon C.; Ravindrarajah, Radhi; Ricketts, Michelle; Waller, Matthew; Weston, Paul; Widaa, Sara; Whittaker, Pamela; Barroso, Ines; Deloukas, Panos; Mathew, Christopher G.; Blackwell, Jenefer M.; Brown, Matthew A.; Corvin, Aiden; McCarthy, Mark I.; Spencer, Chris C. A.

2014-01-01

Statins effectively lower LDL cholesterol levels in large studies and the observed interindividual response variability may be partially explained by genetic variation. Here we perform a pharmacogenetic meta-analysis of genome-wide association studies (GWAS) in studies addressing the LDL cholesterol response to statins, including up to 18,596 statin-treated subjects. We validate the most promising signals in a further 22,318 statin recipients and identify two loci, SORT1/CELSR2/PSRC1 and SLCO1B1, not previously identified in GWAS. Moreover, we confirm the previously described associations with APOE and LPA. Our findings advance the understanding of the pharmacogenetic architecture of statin response. PMID:25350695

Sustaining Research Networks: the Twenty-Year Experience of the HMO Research Network

PubMed Central

Steiner, John F.; Paolino, Andrea R.; Thompson, Ella E.; Larson, Eric B.

2014-01-01

Purpose: As multi-institutional research networks assume a central role in clinical research, they must address the challenge of sustainability. Despite its importance, the concept of network sustainability has received little attention in the literature, and the sustainability strategies of durable scientific networks have not been described. Innovation: The Health Maintenance Organization Research Network (HMORN) is a consortium of 18 research departments in integrated health care delivery systems with over 15 million members in the United States and Israel. The HMORN has coordinated federally funded scientific networks and studies since 1994. This case study describes the HMORN approach to sustainability, proposes an operational definition of network sustainability, and identifies 10 essential elements that can enhance sustainability. Credibility: The sustainability framework proposed here is drawn from prior publications on organizational issues by HMORN investigators and from the experience of recent HMORN leaders and senior staff. Conclusion and Discussion: Network sustainability can be defined as (1) the development and enhancement of shared research assets to facilitate a sequence of research studies in a specific content area or multiple areas, and (2) a community of researchers and other stakeholders who reuse and develop those assets. Essential elements needed to develop the shared assets of a network include: network governance; trustworthy data and processes for sharing data; shared knowledge about research tools; administrative efficiency; physical infrastructure; and infrastructure funding. The community of researchers within a network is enhanced by: a clearly defined mission, vision and values; protection of human subjects; a culture of collaboration; and strong relationships with host organizations. While the importance of these elements varies based on the membership and goals of a network, this framework for sustainability can enhance strategic

Estrogen-Mediated Breast Carcinogenesis: The Role of Sulfation Pharmacogenetics

DTIC Science & Technology

2002-05-01

Final (1 May 99 - 30 Apr 02) 4. TITLE AND SUBTITLE 5 . FUNDING NUMBERS Estrogen-Mediated Breast Carcinogenesis: The DAMD17-99-1-9281 Role of Sulfation...Pharmacogenetics 6 . AUTHOR(S) Araba Adjei, Ph.D. 7. PERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES) 8. PERFORMING ORGANIZATION REPORT NUMBER Mayo...4 IN TR O D U CTIO N ................................................................................................... 5 B O D Y

Pharmacogenomics and pharmacogenetics for the intensive care unit: a narrative review.

PubMed

MacKenzie, Meghan; Hall, Richard

2017-01-01

Knowledge of how alterations in pharmacogenomics and pharmacogenetics may affect drug therapy in the intensive care unit (ICU) has received little study. We review the clinically relevant application of pharmacogenetics and pharmacogenomics to drugs and conditions encountered in the ICU. We selected relevant literature to illustrate the important concepts contained within. Two main approaches have been used to identify genetic abnormalities - the candidate gene approach and the genome-wide approach. Genetic variability in response to drugs may occur as a result of alterations of drug-metabolizing (cytochrome P [CYP]) enzymes, receptors, and transport proteins leading to enhancement or delay in the therapeutic response. Of relevance to the ICU, genetic variation in CYP-450 isoenzymes results in altered effects of midazolam, fentanyl, morphine, codeine, phenytoin, clopidogrel, warfarin, carvedilol, metoprolol, HMG-CoA reductase inhibitors, calcineurin inhibitors, non-steroidal anti-inflammatory agents, proton pump inhibitors, and ondansetron. Changes in cholinesterase enzyme function may affect the disposition of succinylcholine, benzylisoquinoline muscle relaxants, remifentanil, and hydralazine. Genetic variation in transport proteins leads to differences in the response to opioids and clopidogrel. Polymorphisms in drug receptors result in altered effects of β-blockers, catecholamines, antipsychotic agents, and opioids. Genetic variation also contributes to the diversity and incidence of diseases and conditions such as sepsis, malignant hyperthermia, drug-induced hypersensitivity reactions, cardiac channelopathies, thromboembolic disease, and congestive heart failure. Application of pharmacogenetics and pharmacogenomics has seen improvements in drug therapy. Ongoing study and incorporation of these concepts into clinical decision making in the ICU has the potential to affect patient outcomes.

From Human Genetics and Genomics to Pharmacogenetics and Pharmacogenomics: Past Lessons, Future Directions

PubMed Central

Nebert, Daniel W.; Zhang, Ge; Vesell, Elliot S.

2009-01-01

A brief history of human genetics and genomics is provided, comparing recent progress in those fields with that in pharmacogenetics and pharmacogenomics, which are subsets of genetics and genomics, respectively. Sequencing of the entire human genome, the mapping of common haplotypes of single-nucleotide polymorphisms (SNPs), and cost-effective genotyping technologies leading to genome-wide association (GWA) studies—have combined convincingly in the past several years to demonstrate the requirements needed to separate true associations from the plethora of false positives. While research in human genetics has moved from monogenic to oligogenic to complex diseases, its pharmacogenetics branch has followed, usually a few years behind. The continuous discoveries, even today, of new surprises about our genome cause us to question reviews declaring that “personalized medicine is almost here” or that “individualized drug therapy will soon be a reality.” As summarized herein, numerous reasons exist to show that an “unequivocal genotype” or even an “unequivocal phenotype” is virtually impossible to achieve in current limited-size studies of human populations. This problem (of insufficiently stringent criteria) leads to a decrease in statistical power and, consequently, equivocal interpretation of most genotype-phenotype association studies. It remains unclear whether personalized medicine or individualized drug therapy will ever be achievable by means of DNA testing alone. PMID:18464043

Pharmacogenetics of novel oral anticoagulants: a review of identified gene variants & future perspectives.

PubMed

Ašić, Adna; Marjanović, Damir; Mirat, Jure; Primorac, Dragan

2018-05-16

Novel oral anticoagulants (NOACs) are becoming a therapy of choice in everyday clinical practice after almost 50 years during which warfarin and related coumarin derivatives were used as the main anticoagulants. Advantages of NOACs over standard anticoagulants include their predictable pharmacodynamics and pharmacokinetics, stable plasma concentrations and less drug-drug and food-drug interactions. However, pharmacogenetics has its place in administration of NOACs, as considerable interindividual variations have been detected. In this review, previous findings in pharmacogenetics of dabigatran, rivaroxaban, apixaban and edoxaban are summarized, along with recommendations for studying genes encoding metabolically important enzymes for four selected NOACs. Future directions include identification of clinically relevant SNPs, and change in optimum dosage for patients who are carriers of significant variants.

Patient characteristics driving clinical utility in psychiatric pharmacogenetics: a reanalysis from the AB-GEN multicentric trial.

PubMed

Menchón, J M; Espadaler, J; Tuson, M; Saiz-Ruiz, J; Bobes, J; Vieta, E; Álvarez, E; Pérez, V

2018-05-04

Clinical utility of commercial multi-gene pharmacogenetic tests in depression is starting to be studied with some promising results on efficacy and tolerability. Among the next steps is the definition of the patient profile that is most likely to benefit from testing. Here we present a reanalysis of data from the AB-GEN randomized clinical trial showing that clinical utility of pharmacogenetic testing can be markedly influenced by patient characteristics such as age, baseline severity and duration of current depressive episode.Trial registration ClinicalTrials.gov NCT02529462.

Verification of Pharmacogenetics-Based Warfarin Dosing Algorithms in Han-Chinese Patients Undertaking Mechanic Heart Valve Replacement

PubMed Central

Zhao, Li; Chen, Chunxia; Li, Bei; Dong, Li; Guo, Yingqiang; Xiao, Xijun; Zhang, Eryong; Qin, Li

2014-01-01

Objective To study the performance of pharmacogenetics-based warfarin dosing algorithms in the initial and the stable warfarin treatment phases in a cohort of Han-Chinese patients undertaking mechanic heart valve replacement. Methods We searched PubMed, Chinese National Knowledge Infrastructure and Wanfang databases for selecting pharmacogenetics-based warfarin dosing models. Patients with mechanic heart valve replacement were consecutively recruited between March 2012 and July 2012. The predicted warfarin dose of each patient was calculated and compared with the observed initial and stable warfarin doses. The percentage of patients whose predicted dose fell within 20% of their actual therapeutic dose (percentage within 20%), and the mean absolute error (MAE) were utilized to evaluate the predictive accuracy of all the selected algorithms. Results A total of 8 algorithms including Du, Huang, Miao, Wei, Zhang, Lou, Gage, and International Warfarin Pharmacogenetics Consortium (IWPC) model, were tested in 181 patients. The MAE of the Gage, IWPC and 6 Han-Chinese pharmacogenetics-based warfarin dosing algorithms was less than 0.6 mg/day in accuracy and the percentage within 20% exceeded 45% in all of the selected models in both the initial and the stable treatment stages. When patients were stratified according to the warfarin dose range, all of the equations demonstrated better performance in the ideal-dose range (1.88–4.38 mg/day) than the low-dose range (<1.88 mg/day). Among the 8 algorithms compared, the algorithms of Wei, Huang, and Miao showed a lower MAE and higher percentage within 20% in both the initial and the stable warfarin dose prediction and in the low-dose and the ideal-dose ranges. Conclusions All of the selected pharmacogenetics-based warfarin dosing regimens performed similarly in our cohort. However, the algorithms of Wei, Huang, and Miao showed a better potential for warfarin prediction in the initial and the stable treatment phases in Han

Verification of pharmacogenetics-based warfarin dosing algorithms in Han-Chinese patients undertaking mechanic heart valve replacement.

PubMed

Zhao, Li; Chen, Chunxia; Li, Bei; Dong, Li; Guo, Yingqiang; Xiao, Xijun; Zhang, Eryong; Qin, Li

2014-01-01

To study the performance of pharmacogenetics-based warfarin dosing algorithms in the initial and the stable warfarin treatment phases in a cohort of Han-Chinese patients undertaking mechanic heart valve replacement. We searched PubMed, Chinese National Knowledge Infrastructure and Wanfang databases for selecting pharmacogenetics-based warfarin dosing models. Patients with mechanic heart valve replacement were consecutively recruited between March 2012 and July 2012. The predicted warfarin dose of each patient was calculated and compared with the observed initial and stable warfarin doses. The percentage of patients whose predicted dose fell within 20% of their actual therapeutic dose (percentage within 20%), and the mean absolute error (MAE) were utilized to evaluate the predictive accuracy of all the selected algorithms. A total of 8 algorithms including Du, Huang, Miao, Wei, Zhang, Lou, Gage, and International Warfarin Pharmacogenetics Consortium (IWPC) model, were tested in 181 patients. The MAE of the Gage, IWPC and 6 Han-Chinese pharmacogenetics-based warfarin dosing algorithms was less than 0.6 mg/day in accuracy and the percentage within 20% exceeded 45% in all of the selected models in both the initial and the stable treatment stages. When patients were stratified according to the warfarin dose range, all of the equations demonstrated better performance in the ideal-dose range (1.88-4.38 mg/day) than the low-dose range (<1.88 mg/day). Among the 8 algorithms compared, the algorithms of Wei, Huang, and Miao showed a lower MAE and higher percentage within 20% in both the initial and the stable warfarin dose prediction and in the low-dose and the ideal-dose ranges. All of the selected pharmacogenetics-based warfarin dosing regimens performed similarly in our cohort. However, the algorithms of Wei, Huang, and Miao showed a better potential for warfarin prediction in the initial and the stable treatment phases in Han-Chinese patients undertaking mechanic heart

Pharmacogenetics of adverse reactions to antiepileptic drugs.

PubMed

Fricke-Galindo, I; Jung-Cook, H; LLerena, A; López-López, M

2018-04-01

Adverse drug reactions (ADRs) are a major public health concern and a leading cause of morbidity and mortality in the world. In the case of antiepileptic drugs (AEDs), ADRs constitute a barrier to successful treatment since they decrease treatment adherence and impact patients' quality of life of patients. Pharmacogenetics aims to identify genetic polymorphisms associated with drug safety. This article presents a review of genes coding for drug metabolising enzymes and drug transporters, and HLA system genes that have been linked to AED-induced ADRs. To date, several genetic variations associated with drug safety have been reported: CYP2C9*2 and *3 alleles, which code for enzymes with decreased activity, have been linked to phenytoin (PHT)-induced neurotoxicity; GSTM1 null alleles with hepatotoxicity induced by carbamazepine (CBZ) and valproic acid (VPA); EPHX1 polymorphisms with teratogenesis; ABCC2 genetic variations with CBZ- and VPA-induced neurological ADRs; and HLA alleles (e.g. HLA-B*15:02, -A*31:01, -B*15:11, -C*08:01) with cutaneous ADRs. Published findings show that there are ADRs with a pharmacogenetic basis and a high interethnic variability, which indicates a need for future studies in different populations to gather more useful results for larger number of patients. The search for biomarkers that would allow predicting ADRs to AEDs could improve pharmacotherapy for epilepsy. Copyright © 2014 Sociedad Española de Neurología. Publicado por Elsevier España, S.L.U. All rights reserved.

Clinical pharmacogenetics implementation: approaches, successes, and challenges.

PubMed

Weitzel, Kristin W; Elsey, Amanda R; Langaee, Taimour Y; Burkley, Benjamin; Nessl, David R; Obeng, Aniwaa Owusu; Staley, Benjamin J; Dong, Hui-Jia; Allan, Robert W; Liu, J Felix; Cooper-Dehoff, Rhonda M; Anderson, R David; Conlon, Michael; Clare-Salzler, Michael J; Nelson, David R; Johnson, Julie A

2014-03-01

Current challenges exist to widespread clinical implementation of genomic medicine and pharmacogenetics. The University of Florida (UF) Health Personalized Medicine Program (PMP) is a pharmacist-led, multidisciplinary initiative created in 2011 within the UF Clinical Translational Science Institute. Initial efforts focused on pharmacogenetics, with long-term goals to include expansion to disease-risk prediction and disease stratification. Herein we describe the processes for development of the program, the challenges that were encountered and the clinical acceptance by clinicians of the genomic medicine implementation. The initial clinical implementation of the UF PMP began in June 2012 and targeted clopidogrel use and the CYP2C19 genotype in patients undergoing left heart catheterization and percutaneous-coronary intervention (PCI). After 1 year, 1,097 patients undergoing left heart catheterization were genotyped preemptively, and 291 of those underwent subsequent PCI. Genotype results were reported to the medical record for 100% of genotyped patients. Eighty patients who underwent PCI had an actionable genotype, with drug therapy changes implemented in 56 individuals. Average turnaround time from blood draw to genotype result entry in the medical record was 3.5 business days. Seven different third party payors, including Medicare, reimbursed for the test during the first month of billing, with an 85% reimbursement rate for outpatient claims that were submitted in the first month. These data highlight multiple levels of success in clinical implementation of genomic medicine. © 2014 Wiley Periodicals, Inc.

Pharmacogenetics of leptin in antipsychotic-associated weight gain and obesity-related complications

PubMed Central

Lee, Amy K; Bishop, Jefrey R

2013-01-01

Second-generation antipsychotics can greatly improve symptoms of psychosis-spectrum disorders. Unfortunately, these drugs are associated with weight gain, which increases a patient’s risk for developing chronic diseases including Type 2 diabetes, cardiovascular diseases or other obesity-related complications. There are interindividual differences in weight gain resulting from antipsychotic drug use that may be explained by pharmacodynamic characteristics of these agents as well as clinical factors. In addition, genetic variations in pathways associated with satiety are increasingly recognized as potential contributors to antipsychotic-associated weight gain. Polymorphisms in the leptin gene, as well as the leptin receptor gene, are potential pharmacogenetic markers associated with these outcomes. This article summarizes evidence for the associations of the leptin gene and the leptin receptor gene polymorphisms with antipsychotic-induced weight gain, potential mechanisms underlying these relationships, and discusses areas for future pharmacogenetic investigation. PMID:21787190

Anticoagulation Endpoints with Clinical Implementation of Warfarin Pharmacogenetic Dosing in a Real-World Setting – A Proposal for a New Pharmacogenetic Dosing Approach

PubMed Central

Arwood, Meghan J.; Deng, Jiexin; Drozda, Katarzyna; Pugach, Oksana; Nutescu, Edith A.; Schmidt, Stephan; Duarte, Julio D.; Cavallari, Larisa H.

2016-01-01

Achieving therapeutic anticoagulation efficiently with warfarin is important to reduce thrombotic and bleeding risks and is influenced by genotype. Utilizing data from a diverse population of 257 patients who received VKORC1 and CYP2C9 genotype-guided warfarin dosing, we aimed to examine genotype-associated differences in anticoagulation endpoints and derive a novel pharmacogenetic nomogram to more optimally dose warfarin. We observed significant differences across patients with 0, 1, or ≥2 reduced-function VKORC1 or CYP2C9 alleles, respectively, in time to achieve therapeutic international normalized ratio (INR) (7.8±5.8, 7.2±4.7, and 5.4±4.6 days, P=0.0004) and mean percentage of time in therapeutic range in the first 28 days (22.2, 27.8, and 32.2%, P=0.0127) with use of existing pharmacogenetic algorithms. These data suggest that more aggressive dosing is necessary for patients with 0 to 1 VKORC1/CYP2C9 variants to more efficiently achieve therapeutic anticoagulation. Herein, we provide a novel kinetic/pharmacodynamic-derived dosing nomogram optimized for a heterogeneous patient population. PMID:28032893

Abacavir Pharmacogenetics – From Initial Reports to Standard of Care

PubMed Central

Martin, Michael A.; Kroetz, Deanna L.

2013-01-01

Abacavir is a nucleoside analogue reverse transcriptase inhibitor (NRTI) indicated for the treatment of human immunodeficiency virus (HIV) infection as part of a multidrug, highly active antiretroviral therapy (HAART) regimen. Despite its efficacy in treating HIV, approximately 5% of individuals that receive abacavir develop an immune-mediated hypersensitivity reaction (HSR) that warrants immediate discontinuation of abacavir and switching to an alternative antiretroviral regimen. Abacavir HSR is associated with individuals that carry the *57:01 variant in the human leukocyte antigen B (HLA-B) gene. There is a large volume of evidence to show that those who carry HLA-B*57:01 are at significantly increased risk of developing HSR and should not receive abacavir. Using pharmacogenetic screening to ensure individuals who carry y HLA-B*57:01 do not receive abacavir can reduce the incidence of abacavir HSR and is now considered the standard of care before prescribing abacavir. Genetic testing for abacavir HSR is currently one of the best examples of integrating pharmacogenetic testing into clinical practice. PMID:23649914

Pharmacoeconomic evaluations of pharmacogenetic and genomic screening programmes: a systematic review on content and adherence to guidelines.

PubMed

Vegter, Stefan; Boersma, Cornelis; Rozenbaum, Mark; Wilffert, Bob; Navis, Gerjan; Postma, Maarten J

2008-01-01

The fields of pharmacogenetics and pharmacogenomics have become important practical tools to progress goals in medical and pharmaceutical research and development. As more screening tests are being developed, with some already used in clinical practice, consideration of cost-effectiveness implications is important. A systematic review was performed on the content of and adherence to pharmacoeconomic guidelines of recent pharmacoeconomic analyses performed in the field of pharmacogenetics and pharmacogenomics. Economic analyses of screening strategies for genetic variations, which were evidence-based and assumed to be associated with drug efficacy or safety, were included in the review. The 20 papers included cover a variety of healthcare issues, including screening tests on several cytochrome P450 (CYP) enzyme genes, thiopurine S-methyltransferase (TMPT) and angiotensin-converting enzyme (ACE) insertion deletion (ACE I/D) polymorphisms. Most economic analyses reported that genetic screening was cost effective and often even clearly dominated existing non-screening strategies. However, we found a lack of standardization regarding aspects such as the perspective of the analysis, factors included in the sensitivity analysis and the applied discount rates. In particular, an important limitation of several studies related to the failure to provide a sufficient evidence-based rationale for an association between genotype and phenotype. Future economic analyses should be conducted utilizing correct methods, with adherence to guidelines and including extensive sensitivity analyses. Most importantly, genetic screening strategies should be based on good evidence-based rationales. For these goals, we provide a list of recommendations for good pharmacoeconomic practice deemed useful in the fields of pharmacogenetics and pharmacogenomics, regardless of country and origin of the economic analysis.

Economics of Pharmacogenetic-Guided Treatments: Underwhelming or Overstated?

PubMed

Hughes, Dyfrig A

2018-05-01

Economic evaluations have dispelled a perception that precision medicine, achieved through pharmacogenetic testing, reduces healthcare costs. For many tests aimed at preventing adverse drug reactions, cost-effectiveness analyses predict modest improvements in health benefits and increases in total costs. While there are many uncertainties in estimating the value of testing, factors that influence cost-effectiveness include the rarity of the outcome, the effectiveness of alternative treatments, and the scope and perspective of analysis. © 2018 ASCPT.

Pharmacogenetics of tacrolimus and sirolimus in renal transplant patients: from retrospective analyses to prospective studies.

PubMed

Anglicheau, D; Legendre, C; Thervet, E

2007-09-01

The promises of pharmacogenetics are to elucidate the inherited basis of differences between individual responses to drugs in order to identify the right drug and dose for each patient. The recent identification of genetic polymorphisms in drug-metabolizing enzymes and drug transporters led to the hypothesis that genetic factors may be implicated in the interindividual variability of the pharmacokinetic or pharmacodynamic characteristics of immunosuppressive drugs, major side effects, and efficacy. The purpose of this study was to provide a short overview of recent results obtained in the field of pharmacogenetics of tacrolimus and sirolimus, both substrates of the cytochrome P450 3A (CYP3A) enzymes and of the efflux pump P-glycoprotein, the product of the Multidrug Resistance-1 (MDR1) genes. A number of retrospective studies that demonstrated a link between the polymorphisms governing the CYP3A5 protein expression, with more conflicting results with the MDR1 gene polymorphisms, related to the daily dose necessary to achieve adequate blood tacrolimus levels. The CYP3A5 polymorphisms have also been associated with sirolimus pharmacokinetics. One challenge is to investigate the combined effect of a number of different polymorphisms in various genes to define genetic backgrounds with different pharmacokinetic profiles using high throughput technologies. Another challenge is to move toward prospective randomized studies to explore whether a pharmacogenetic approach, taking into account a limited number of polymorphisms prior to drug treatment, could be used on an individual basis to guide initial dosing of a given drug. The last challenge is based on "target" pharmacogenetics to investigate the role of the polymorphisms of other genes implicated in the efficacy and/or safety of the drug.

A Pharmacogenetic Screening Experiment Demonstrating Principles of Genetic Constitution on Drug Metabolism.

ERIC Educational Resources Information Center

Robbins, Doris K.; Wedlund, Peter J.

1990-01-01

A laboratory experiment designed to provide rapid, inexpensive student exposure to pharmacogenetics in drug elimination and patient therapy is described. The test, performed on students, determines expression of a drug metabolism enzyme following ingestion of a probe drug. (Author/MSE)

Outcome definitions and clinical predictors influence pharmacogenetic associations between HTR3A gene polymorphisms and response to clozapine in patients with schizophrenia.

PubMed

Rajkumar, A P; Poonkuzhali, B; Kuruvilla, A; Srivastava, A; Jacob, M; Jacob, K S

2012-12-01

Pharmacogenetics of schizophrenia has not yet delivered anticipated clinical dividends. Clinical heterogeneity of schizophrenia contributes to the poor replication of the findings of pharmacogenetic association studies. Functionally important HTR3A gene single-nucleotide polymorphisms (SNPs) were reported to be associated with response to clozapine. The aim of this study was to investigate how the association between HTR3A gene SNP and response to clozapine is influenced by various clinical predictors and by differing outcome definitions in patients with treatment-resistant schizophrenia (TRS). We recruited 101 consecutive patients with TRS, on stable doses of clozapine, and evaluated their HTR3A gene SNP (rs1062613 and rs2276302), psychopathology, and serum clozapine levels. We assessed their socio-demographic and clinical profiles, premorbid adjustment, traumatic events, cognition, and disability using standard assessment schedules. We evaluated their response to clozapine, by employing six differing outcome definitions. We employed appropriate multivariate statistics to calculate allelic and genotypic association, accounting for the effects of various clinical variables. T allele of rs1062613 and G allele of rs2276302 were significantly associated with good clinical response to clozapine (p = 0.02). However, varying outcome definitions make these associations inconsistent. rs1062613 and rs2276302 could explain only 13.8 % variability in the responses to clozapine, while combined clinical predictors and HTR3A pharmacogenetic association model could explain 38 % variability. We demonstrated that the results of pharmacogenetic studies in schizophrenia depend heavily on their outcome definitions and that combined clinical and pharmacogenetic models have better predictive values. Future pharmacogenetic studies should employ multiple outcome definitions and should evaluate associated clinical variables.

Medical education practice-based research networks: Facilitating collaborative research.

PubMed

Schwartz, Alan; Young, Robin; Hicks, Patricia J

2016-01-01

Research networks formalize and institutionalize multi-site collaborations by establishing an infrastructure that enables network members to participate in research, propose new studies, and exploit study data to move the field forward. Although practice-based clinical research networks are now widespread, medical education research networks are rapidly emerging. In this article, we offer a definition of the medical education practice-based research network, a brief description of networks in existence in July 2014 and their features, and a more detailed case study of the emergence and early growth of one such network, the Association of Pediatric Program Directors Longitudinal Educational Assessment Research Network (APPD LEARN). We searched for extant networks through peer-reviewed literature and the world-wide web. We identified 15 research networks in medical education founded since 2002 with membership ranging from 8 to 120 programs. Most focus on graduate medical education in primary care or emergency medicine specialties. We offer four recommendations for the further development and spread of medical education research networks: increasing faculty development, obtaining central resources, studying networks themselves, and developing networks of networks.

Medical education practice-based research networks: Facilitating collaborative research

PubMed Central

Schwartz, Alan; Young, Robin; Hicks, Patricia J.; APPD LEARN, For

2016-01-01

Abstract Background: Research networks formalize and institutionalize multi-site collaborations by establishing an infrastructure that enables network members to participate in research, propose new studies, and exploit study data to move the field forward. Although practice-based clinical research networks are now widespread, medical education research networks are rapidly emerging. Aims: In this article, we offer a definition of the medical education practice-based research network, a brief description of networks in existence in July 2014 and their features, and a more detailed case study of the emergence and early growth of one such network, the Association of Pediatric Program Directors Longitudinal Educational Assessment Research Network (APPD LEARN). Methods: We searched for extant networks through peer-reviewed literature and the world-wide web. Results: We identified 15 research networks in medical education founded since 2002 with membership ranging from 8 to 120 programs. Most focus on graduate medical education in primary care or emergency medicine specialties. Conclusions: We offer four recommendations for the further development and spread of medical education research networks: increasing faculty development, obtaining central resources, studying networks themselves, and developing networks of networks. PMID:25319404

Implementation of a pharmacogenetic management service for postmyocardial infarction care in a community pharmacy.

PubMed

Bright, D R; Kisor, D F; Smith, A; Conaway, M; Yu, M

2015-08-01

The purpose of this study was to pilot a multisite, proof-of-concept model where community pharmacists could engage patients and physicians to provide pharmacogenetic (PGt) testing and clinical decision support. Patients with history of acute myocardial infarction and percutaneous coronary intervention with no prior history of CYP2C19 testing. Four community pharmacies provided pharmacogenetic testing and medication therapy management services to 30 patients, resulting in eight recommendations for antiplatelet therapy adjustment. Pharmacists involved in the study were able to facilitate antiplatelet therapy adjustments based on PGt data regardless of baseline antiplatelet drug selection. Whereas prior literature largely revolved around PGt management in the inpatient setting, this project supports the involvement of the community pharmacist in making PGt-based recommendations.

Pharmacogenetics of drugs withdrawn from the market.

PubMed

Zhang, Wei; Roederer, Mary W; Chen, Wang-Qing; Fan, Lan; Zhou, Hong-Hao

2012-01-01

The safety and efficacy of candidate compounds are critical factors during the development of drugs, and most drugs have been withdrawn from the market owing to severe adverse reactions. Individuals/populations with different genetic backgrounds may show significant differences in drug metabolism and efficacy, which can sometimes manifest as severe adverse drug reactions. With an emphasis on the mechanisms underlying abnormal drug effects caused by genetic mutations, pharmacogenetic studies may enhance the safety and effectiveness of drug use, provide more comprehensive delineations of the scope of usage, and change the fates of drugs withdrawn from the market.

Using local multiplicity to improve effect estimation from a hypothesis-generating pharmacogenetics study.

PubMed

Zou, W; Ouyang, H

2016-02-01

We propose a multiple estimation adjustment (MEA) method to correct effect overestimation due to selection bias from a hypothesis-generating study (HGS) in pharmacogenetics. MEA uses a hierarchical Bayesian approach to model individual effect estimates from maximal likelihood estimation (MLE) in a region jointly and shrinks them toward the regional effect. Unlike many methods that model a fixed selection scheme, MEA capitalizes on local multiplicity independent of selection. We compared mean square errors (MSEs) in simulated HGSs from naive MLE, MEA and a conditional likelihood adjustment (CLA) method that model threshold selection bias. We observed that MEA effectively reduced MSE from MLE on null effects with or without selection, and had a clear advantage over CLA on extreme MLE estimates from null effects under lenient threshold selection in small samples, which are common among 'top' associations from a pharmacogenetics HGS.

Pharmacogenetic studies of antidepressant response: how far from the clinic?

PubMed

Perlis, Roy H

2007-03-01

Because the US FDA has begun to focus on disclosure of pharmacogenetic testing results in applications for new drug approval and review of existing drugs (see, eg, http://www.fda.gov/OHRMS/DOCKETS/AC/05/slides/2005-4194S1_Slide-Index.htm), the application of such testing in a clinical setting is likely to increase substantially. Instead of small cohorts of patients, potentially nearly every participant in the large pivotal trials required for drug approval could help inform the future application of that drug. Psychiatry as a whole, and antidepressant prescribing ni particular, stands to benefit in the near term from the identification of newer treatment targets that may overcome some of the limitations of current therapeutics. On the other hand, despite the excitement about the rapid pace of development in psychiatric pharmacogenetics, a number of key issues remain to be addressed before these discoveries are applied in a clinical setting. Close coordination will be required between those who study treatment efficacy and effectiveness and those who study genetic variation in populations to ensure that studies yield results that have scientific importance and clinical importance as well.

The Pharmacogenetics of Type 2 Diabetes: A Systematic Review

PubMed Central

Maruthur, Nisa M.; Gribble, Matthew O.; Bennett, Wendy L.; Bolen, Shari; Wilson, Lisa M.; Balakrishnan, Poojitha; Sahu, Anita; Bass, Eric; Kao, W.H. Linda; Clark, Jeanne M.

2014-01-01

OBJECTIVE We performed a systematic review to identify which genetic variants predict response to diabetes medications. RESEARCH DESIGN AND METHODS We performed a search of electronic databases (PubMed, EMBASE, and Cochrane Database) and a manual search to identify original, longitudinal studies of the effect of diabetes medications on incident diabetes, HbA1c, fasting glucose, and postprandial glucose in prediabetes or type 2 diabetes by genetic variation. Two investigators reviewed titles, abstracts, and articles independently. Two investigators abstracted data sequentially and evaluated study quality independently. Quality evaluations were based on the Strengthening the Reporting of Genetic Association Studies guidelines and Human Genome Epidemiology Network guidance. RESULTS Of 7,279 citations, we included 34 articles (N = 10,407) evaluating metformin (n = 14), sulfonylureas (n = 4), repaglinide (n = 8), pioglitazone (n = 3), rosiglitazone (n = 4), and acarbose (n = 4). Studies were not standalone randomized controlled trials, and most evaluated patients with diabetes. Significant medication–gene interactions for glycemic outcomes included 1) metformin and the SLC22A1, SLC22A2, SLC47A1, PRKAB2, PRKAA2, PRKAA1, and STK11 loci; 2) sulfonylureas and the CYP2C9 and TCF7L2 loci; 3) repaglinide and the KCNJ11, SLC30A8, NEUROD1/BETA2, UCP2, and PAX4 loci; 4) pioglitazone and the PPARG2 and PTPRD loci; 5) rosiglitazone and the KCNQ1 and RBP4 loci; and 5) acarbose and the PPARA, HNF4A, LIPC, and PPARGC1A loci. Data were insufficient for meta-analysis. CONCLUSIONS We found evidence of pharmacogenetic interactions for metformin, sulfonylureas, repaglinide, thiazolidinediones, and acarbose consistent with their pharmacokinetics and pharmacodynamics. While high-quality controlled studies with prespecified analyses are still lacking, our results bring the promise of personalized medicine in diabetes one step closer to fruition. PMID:24558078

DNA cards: determinants of DNA yield and quality in collecting genetic samples for pharmacogenetic studies.

PubMed

Mas, Sergi; Crescenti, Anna; Gassó, Patricia; Vidal-Taboada, Jose M; Lafuente, Amalia

2007-08-01

As pharmacogenetic studies frequently require establishment of DNA banks containing large cohorts with multi-centric designs, inexpensive methods for collecting and storing high-quality DNA are needed. The aims of this study were two-fold: to compare the amount and quality of DNA obtained from two different DNA cards (IsoCode Cards or FTA Classic Cards, Whatman plc, Brentford, Middlesex, UK); and to evaluate the effects of time and storage temperature, as well as the influence of anticoagulant ethylenediaminetetraacetic acid on the DNA elution procedure. The samples were genotyped by several methods typically used in pharmacogenetic studies: multiplex PCR, PCR-restriction fragment length polymorphism, single nucleotide primer extension, and allelic discrimination assay. In addition, they were amplified by whole genome amplification to increase genomic DNA mass. Time, storage temperature and ethylenediaminetetraacetic acid had no significant effects on either DNA card. This study reveals the importance of drying blood spots prior to isolation to avoid haemoglobin interference. Moreover, our results demonstrate that re-isolation protocols could be applied to increase the amount of DNA recovered. The samples analysed were accurately genotyped with all the methods examined herein. In conclusion, our study shows that both DNA cards, IsoCode Cards and FTA Classic Cards, facilitate genetic and pharmacogenetic testing for routine clinical practice.

Pharmacogenetics Informed Decision Making in Adolescent Psychiatric Treatment: A Clinical Case Report

PubMed Central

Smith, Teri; Sharp, Susan; Manzardo, Ann M.; Butler, Merlin G.

2015-01-01

Advances made in genetic testing and tools applied to pharmacogenetics are increasingly being used to inform clinicians in fields such as oncology, hematology, diabetes (endocrinology), cardiology and expanding into psychiatry by examining the influences of genetics on drug efficacy and metabolism. We present a clinical case example of an adolescent male with anxiety, attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder who did not tolerate numerous medications and dosages over several years in attempts to manage his symptoms. Pharmacogenetics testing was performed and DNA results on this individual elucidated the potential pitfalls in medication use because of specific pharmacodynamic and pharmacokinetic differences specifically involving polymorphisms of genes in the cytochrome p450 enzyme system. Future studies and reports are needed to further illustrate and determine the type of individualized medicine approach required to treat individuals based on their specific gene patterns. Growing evidence supports this biological approach for standard of care in psychiatry. PMID:25710722

The role of depression pharmacogenetic decision support tools in shared decision making.

PubMed

Arandjelovic, Katarina; Eyre, Harris A; Lenze, Eric; Singh, Ajeet B; Berk, Michael; Bousman, Chad

2017-10-29

Patients discontinue antidepressant medications due to lack of knowledge, unrealistic expectations, and/or unacceptable side effects. Shared decision making (SDM) invites patients to play an active role in their treatment and may indirectly improve outcomes through enhanced engagement in care, adherence to treatment, and positive expectancy of medication outcomes. We believe decisional aids, such as pharmacogenetic decision support tools (PDSTs), facilitate SDM in the clinical setting. PDSTs may likewise predict drug tolerance and efficacy, and therefore adherence and effectiveness on an individual-patient level. There are several important ethical considerations to be navigated when integrating PDSTs into clinical practice. The field requires greater empirical research to demonstrate clinical utility, and the mechanisms thereof, as well as exploration of the ethical use of these technologies.

Pharmacogenetics in clinical practice: how far have we come and where are we going?

PubMed Central

Johnson, Julie A

2013-01-01

Recent years have seen great advances in our understanding of genetic contributors to drug response. Drug discovery and development around targeted genetic (somatic) mutations has led to a number of new drugs with genetic indications, particularly for the treatment of cancers. Our knowledge of genetic contributors to variable drug response for existing drugs has also expanded dramatically, such that the evidence now supports clinical use of genetic data to guide treatment in some situations, and across a variety of therapeutic areas. Clinical implementation of pharmacogenetics has seen substantial growth in recent years and groups are working to identify the barriers and best practices for pharmacogenetic-guided treatment. The advances and challenges in these areas are described and predictions about future use of genetics in drug therapy are discussed. PMID:23651030

Various pharmacogenetic aspects of antiepileptic drug therapy: a review.

PubMed

Mann, Michael W; Pons, Gerard

2007-01-01

Pharmacogenetics concerns the influence of an individual's genetic background on the pharmacokinetics and pharmacodynamics of xenobiotics. Much of the pharmacogenetic data in the field of epilepsy deals with the pharmacokinetics of antiepileptic drugs (AEDs). In particular, two polymorphisms of cytochrome P450 2C9 are known to slow down the metabolism of phenytoin to a degree that increases the risk of the neurotoxic adverse effects of this drug among carriers of these polymorphisms. A significant number of patients with epilepsy do not respond to AEDs and such pharmacoresistance is a major, largely unsolved, problem that is likely to be multifactorial in nature. In this regard, genetic factors may influence transmembrane drug transporter proteins, thereby modifying the intracerebral penetration of AEDs. Monogenic idiopathic epilepsies are rare and frequently associated with ion channel mutations; however, to date, a consistent relationship between changes in channel properties and clinical phenotype has not been established nor has any association between genotype and response to specific treatment options. Polymorphisms of drug targets may represent another genetic facet in epilepsy: a recent study demonstrated for the first time a polymorphism of a drug target (the alpha-subunit of a voltage-gated sodium channel) associated in clinical practice with differing response to two classic AEDs. Adverse drug reactions and teratogenicity of AEDs remain a major concern. Whole-genome single nucleotide polymorphism profiling might in the future help to determine genetic predisposing factors for adverse drug reactions. Recently, in Han Chinese treated with carbamazepine and presenting with Stevens-Johnson syndrome, a strong association was found with HLA B*1502. If genetically targeted drug development becomes more affordable/cost efficient in the near future, the development of new drugs for relatively rare diseases could become economically viable for the pharmaceutical

Pharmacogenetics of healthy volunteers in Puerto Rico

PubMed Central

Claudio-Campos, Karla; Orengo-Mercado, Carmelo; Renta, Jessicca Y.; Peguero, Muriel; García, Ricardo; Hernández, Gabriel; Corey, Susan; Cadilla, Carmen L.; Duconge, Jorge

2016-01-01

Puerto Ricans are a unique Hispanic population with European, Native American (Taino), and higher West African ancestral contributions than other non-Caribbean Hispanics. In admixed populations, such as Puerto Ricans, genetic variants can be found at different frequencies when compared to parental populations and uniquely combined and distributed. Therefore, in this review, we aimed to collect data from studies conducted in healthy Puerto Ricans and to report the frequencies of genetic polymorphisms with major relevance in drug response. Filtering for healthy volunteers or individuals, we performed a search of pharmacogenetic studies in academic literature databases without limiting the period of the results. The search was limited to Puerto Ricans living in the island, excluding those studies performed in mainland (United States). We found that the genetic markers impacting pharmacological therapy in the areas of cardiovascular, oncology, and neurology are the most frequently investigated. Coincidently, the top causes of mortality in the island are cardiovascular diseases, cancer, diabetes, Alzheimer’s disease, and stroke. In addition, polymorphisms in genes that encode for members of the CYP450 family (CYP2C9, CYP2C19, and CYP2D6) are also available due to their relevance in the metabolism of drugs. The complex genetic background of Puerto Ricans is responsible for the divergence in the reported allele frequencies when compared to parental populations (Africans, East Asians, and Europeans). The importance of reporting the findings of pharmacogenetic studies conducted in Puerto Ricans is to identify genetic variants with potential utility among this genetically complex population and eventually move forward the adoption of personalized medicine in the island. PMID:26501165

Pharmacogenetics of healthy volunteers in Puerto Rico.

PubMed

Claudio-Campos, Karla; Orengo-Mercado, Carmelo; Renta, Jessicca Y; Peguero, Muriel; García, Ricardo; Hernández, Gabriel; Corey, Susan; Cadilla, Carmen L; Duconge, Jorge

2015-12-01

Puerto Ricans are a unique Hispanic population with European, Native American (Taino), and higher West African ancestral contributions than other non-Caribbean Hispanics. In admixed populations, such as Puerto Ricans, genetic variants can be found at different frequencies when compared to parental populations and uniquely combined and distributed. Therefore, in this review, we aimed to collect data from studies conducted in healthy Puerto Ricans and to report the frequencies of genetic polymorphisms with major relevance in drug response. Filtering for healthy volunteers or individuals, we performed a search of pharmacogenetic studies in academic literature databases without limiting the period of the results. The search was limited to Puerto Ricans living in the island, excluding those studies performed in mainland (United States). We found that the genetic markers impacting pharmacological therapy in the areas of cardiovascular, oncology, and neurology are the most frequently investigated. Coincidently, the top causes of mortality in the island are cardiovascular diseases, cancer, diabetes, Alzheimer's disease, and stroke. In addition, polymorphisms in genes that encode for members of the CYP450 family (CYP2C9, CYP2C19, and CYP2D6) are also available due to their relevance in the metabolism of drugs. The complex genetic background of Puerto Ricans is responsible for the divergence in the reported allele frequencies when compared to parental populations (Africans, East Asians, and Europeans). The importance of reporting the findings of pharmacogenetic studies conducted in Puerto Ricans is to identify genetic variants with potential utility among this genetically complex population and eventually move forward the adoption of personalized medicine in the island.

Databases in the Area of Pharmacogenetics

PubMed Central

Sim, Sarah C.; Altman, Russ B.; Ingelman-Sundberg, Magnus

2012-01-01

In the area of pharmacogenetics and personalized health care it is obvious that databases, providing important information of the occurrence and consequences of variant genes encoding drug metabolizing enzymes, drug transporters, drug targets, and other proteins of importance for drug response or toxicity, are of critical value for scientists, physicians, and industry. The primary outcome of the pharmacogenomic field is the identification of biomarkers that can predict drug toxicity and drug response, thereby individualizing and improving drug treatment of patients. The drug in question and the polymorphic gene exerting the impact are the main issues to be searched for in the databases. Here, we review the databases that provide useful information in this respect, of benefit for the development of the pharmacogenomic field. PMID:21309040

Pharmacogenetic aspects of drug-induced torsade de pointes: potential tool for improving clinical drug development and prescribing.

PubMed

Shah, Rashmi R

2004-01-01

Drug-induced torsade de pointes (TdP) has proved to be a significant iatro-genic cause of morbidity and mortality and a major reason for the withdrawal of a number of drugs from the market in recent times. Enzymes that metabolise many of these drugs and the potassium channels that are responsible for cardiac repolarisation display genetic polymorphisms. Anecdotal reports have suggested that in many cases of drug-induced TdP, there may be a concealed genetic defect of either these enzymes or the potassium channels, giving rise to either high plasma drug concentrations or diminished cardiac repolarisation reserve, respectively. The presence of either of these genetic defects may predispose a patient to TdP, a potentially fatal adverse reaction, even at therapeutic dosages of QT-prolonging drugs and in the absence of other risk factors. Advances in pharmacogenetics of drug metabolising enzymes and pharmacological targets, together with the prospects of rapid and inexpensive genotyping procedures, promise to individualise and improve the benefit/risk ratio of therapy with drugs that have the potential to cause TdP. The qualitative and the quantitative contributions of these genetic defects in clinical cases of TdP are unclear because not all of the patients with TdP are routinely genotyped and some relevant genetic mutations still remain to be discovered. There are regulatory guidelines that recommend strategies aimed at uncovering the risk of TdP associated with new chemical entities during their development. There are also a number of guidelines that recommend integrating pharmacogenetics in this process. This paper proposes a strategy for integrating pharmacogenetics into drug development programmes to optimise association studies correlating genetic traits and endpoints of clinical interest, namely failure of efficacy or development of repolarisation abnormalities. Until pharmacogenetics is carefully integrated into all phases of development of QT-prolonging drugs

Methotrexate-induced toxicity pharmacogenetics: an umbrella review of systematic reviews and meta-analyses.

PubMed

Campbell, Jared M; Bateman, Emma; Stephenson, Matthew D; Bowen, Joanne M; Keefe, Dorothy M; Peters, Micah D J

2016-07-01

Methotrexate chemotherapy is associated with various toxicities which can result in the interruption or discontinuation of treatment and a subsequently raised risk of relapse. This umbrella systematic review was conducted to synthesize the results of all existing systematic reviews that investigate the pharmacogenetics of methotrexate-induced toxicity, with the aim of developing a comprehensive reference for personalized medicine. Databases searched were PubMed, Embase, JBI Database of Systematic Reviews and Implementation Reports, DARE, and ProQuest. Papers were critically appraised by two reviewers, and data were extracted using a standardized tool. Three systematic reviews on methotrexate-induced toxicity were included in the review. Meta-analyses were reported across Asian, Caucasian, pediatric and adult patients for the MTHFR C677T and A1298C polymorphisms. Toxicity outcomes included different forms of hematologic, ectodermal and hepatic toxicities. Results varied considerably depending on the patient groups and subgroups investigated in the different systematic reviews, as well as the genetic models utilized. However, significant associations were found between the MTHFR C677T allele and; hepatic toxicity, myelosuppression, oral mucositis, gastrointestinal toxicity, and skin toxicity. Additionally, limited evidence suggests that the MTHFR A1298C polymorphism may be associated with decreased risk of skin toxicity and leukopenia. This umbrella systematic review has synthesized the best available evidence on the pharmacogenetics of methotrexate toxicity. The next step in making personalized medicine for methotrexate therapy a clinical reality is research on the effectiveness and cost-effectiveness of MTHFR genotype testing to enable the close monitoring of at-risk patients for the timely initiation of rescue therapies.

Distinguishing rational from irrational applications of pharmacogenetic synergies from the bench to clinical trials.

PubMed

Hucl, Tomas; Gallmeier, Eike; Kern, Scott E

2007-06-01

Single therapeutic agents very often fail in unselected patients. It is therefore commonplace to combine an agent specifically with a selected patient subgroup or with another agent. To support such efforts, it is useful to clarify the distinctions between the terms and the mathematical models used in analyzing combinations. To incorporate molecular disease classifications, the familiar concept of the therapeutic window is modified to define a pharmacogenetic window, which is an unambiguous numerical measure of the magnitude of interaction produced by a combination, and to define a test of pharmacogenetic synergy. In contrast, certain common comparative methods, such as vertical windows (comparing effects at a given dose) and animal models of mutational targets may be dominated by undesirable features. Although this discussion is oriented towards cancer therapy, an extension of these concepts to other comparative biologic assays is feasible and advisable.

Importance of pharmacogenetics in the treatment of children with attention deficit hyperactive disorder: a case report.

PubMed

Tan-Kam, Teerarat; Suthisisang, Chutamanee; Pavasuthipaisit, Chosita; Limsila, Penkhae; Puangpetch, Apichaya; Sukasem, Chonlaphat

2013-01-01

This case report highlights the importance of pharmacogenetic testing in the treatment of attention deficit hyperactive disorder (ADHD). A 6-year-old boy diagnosed with ADHD was prescribed methylphenidate 5 mg twice daily (7 am and noon) and the family was compliant with administration of this medication. On the first day of treatment, the patient had an adverse reaction, becoming disobedient, more mischievous, erratic, resistant to discipline, would not go to sleep until midnight, and had a poor appetite. The All-In-One PGX (All-In-One Pharmacogenetics for Antipsychotics test for CYP2D6, CYP2C19, and CYP2C9) was performed using microarray-based and real-time polymerase chain reaction techniques. The genotype of our patient was identified to be CYP2D6*2/*10, with isoforms of the enzyme consistent with a predicted cytochrome P450 2D6 intermediate metabolizer phenotype. Consequently, the physician adjusted the methylphenidate dose to 2.5 mg once daily in the morning. At this dosage, the patient had a good response without any further adverse reactions. Pharmacogenetic testing should be included in the management plan for ADHD. In this case, cooperation between the medical team and the patients' relatives was key to successful treatment.

Pharmacogenetics and pharmacogenomics in psoriasis treatment: current challenges and future prospects.

PubMed

Sutherland, Alison; Power, Rebecca J; Rahman, Proton; O'Rielly, Darren D

2016-08-01

Topical, systemic, oral disease modifying, and biologic agents are part of the armamentarium to manage psoriatic disease. The choice of therapy depends upon disease severity, relevant co-morbidities and patient preference. There is great variability in patient response with these agents, and there is still no clear method of selecting the preferred therapeutic agent for efficacy or lack of adverse events. This article will review the pharmacogenetic and pharmacogenomic targets that are currently known with respect to psoriasis vulgaris, and the most frequent co-morbidity of psoriasis, psoriatic arthritis. Presently, no clinically actionable biomarker exists for any therapeutic agent used to treat psoriasis or psoriatic arthritis. The lack of validated outcome measures and conflicting results of open-label studies conducted may be attributed to a multitude of issues that confound discovery. Consequently, studies have been underpowered to identify genes or genetic variants worth translating to clinical practice. In order to achieve a pharmacogenetic/pharmacogenomic signature, improvements in study design of future investigations are required, including carefully designed prospective studies. It is imperative to combine known clinical, serological, and molecular markers with consistent outcomes and an adequate health economic evaluation before they can be adopted widely in clinical practice.

Molecular Classification and Pharmacogenetics of Primary Plasma Cell Leukemia: An Initial Approach toward Precision Medicine

PubMed Central

Simeon, Vittorio; Todoerti, Katia; La Rocca, Francesco; Caivano, Antonella; Trino, Stefania; Lionetti, Marta; Agnelli, Luca; De Luca, Luciana; Laurenzana, Ilaria; Neri, Antonino; Musto, Pellegrino

2015-01-01

Primary plasma cell leukemia (pPCL) is a rare and aggressive variant of multiple myeloma (MM) which may represent a valid model for high-risk MM. This disease is associated with a very poor prognosis, and unfortunately, it has not significantly improved during the last three decades. New high-throughput technologies have allowed a better understanding of the molecular basis of this disease and moved toward risk stratification, providing insights for targeted therapy studies. This knowledge, added to the pharmacogenetic profile of new and old agents in the analysis of efficacy and safety, could contribute to help clinical decisions move toward a precision medicine and a better clinical outcome for these patients. In this review, we describe the available literature concerning the genomic characterization and pharmacogenetics of plasma cell leukemia (PCL). PMID:26263974

Molecular Classification and Pharmacogenetics of Primary Plasma Cell Leukemia: An Initial Approach toward Precision Medicine.

PubMed

Simeon, Vittorio; Todoerti, Katia; La Rocca, Francesco; Caivano, Antonella; Trino, Stefania; Lionetti, Marta; Agnelli, Luca; De Luca, Luciana; Laurenzana, Ilaria; Neri, Antonino; Musto, Pellegrino

2015-07-30

Primary plasma cell leukemia (pPCL) is a rare and aggressive variant of multiple myeloma (MM) which may represent a valid model for high-risk MM. This disease is associated with a very poor prognosis, and unfortunately, it has not significantly improved during the last three decades. New high-throughput technologies have allowed a better understanding of the molecular basis of this disease and moved toward risk stratification, providing insights for targeted therapy studies. This knowledge, added to the pharmacogenetic profile of new and old agents in the analysis of efficacy and safety, could contribute to help clinical decisions move toward a precision medicine and a better clinical outcome for these patients. In this review, we describe the available literature concerning the genomic characterization and pharmacogenetics of plasma cell leukemia (PCL).

Attention-deficit hyperactivity disorder in adults: A systematic review and meta-analysis of genetic, pharmacogenetic and biochemical studies

PubMed Central

Bonvicini, C; Faraone, S V; Scassellati, C

2016-01-01

found for salivary cortisol, whereas lower serum docosahexaenoic acid (DHA) levels were found in ADHD adults. This last association was significant even after Bonferroni correction and in absence of heterogeneity. Other polyunsaturated fatty acids (PUFAs) such as AA (arachidonic acid), EPA (eicosapentaenoic acid) and DyLA (dihomogammalinolenic acid) levels were not different between patients and controls. No publication biases were observed for these markers. Genes linked to dopaminergic, serotoninergic and noradrenergic signaling, metabolism (DBH, TPH1, TPH2, DDC, MAOA, MAOB, BCHE and TH), neurodevelopment (BDNF and others), the SNARE system and other forty genes/proteins related to different pathways were not meta-analyzed due to insufficient data. In conclusion, we found that there were not enough genetic, pharmacogenetic and biochemical studies of ADHD in adults and that more investigations are needed. Moreover we confirmed a significant role of BAIAP2 and DHA in the etiology of ADHD exclusively in adults. Future research should be focused on the replication of these findings and to assess their specificity for ADHD. PMID:27217152

Naltrexone for the treatment of alcoholism: clinical findings, mechanisms of action, and pharmacogenetics.

PubMed

Ray, Lara A; Chin, Pauline F; Miotto, Karen

2010-03-01

Naltrexone is an opioid receptor antagonist with established efficacy, albeit moderate, for the treatment of alcohol dependence. This manuscript provides a critical review of the literature on naltrexone as a pharmacotherapy for alcoholism by covering the following areas: (a) clinical findings from treatment studies; (b) pharmacokinetics and safety data; (c) medication compliance and persistence; and (d) neurobiological and biobehavioral mechanisms of action of naltrexone for the indication of alcohol dependence. This review will then focus on the emerging literature on naltrexone pharmacogenetics, which has the potential to identify responders on the basis of genetic variation and to use genetic tools to individualize the use of this medication. Limitations and future directions in the research and practice of naltrexone for alcoholism are also outlined.

Accuracy assessment of pharmacogenetically predictive warfarin dosing algorithms in patients of an academic medical center anticoagulation clinic.

PubMed

Shaw, Paul B; Donovan, Jennifer L; Tran, Maichi T; Lemon, Stephenie C; Burgwinkle, Pamela; Gore, Joel

2010-08-01

The objectives of this retrospective cohort study are to evaluate the accuracy of pharmacogenetic warfarin dosing algorithms in predicting therapeutic dose and to determine if this degree of accuracy warrants the routine use of genotyping to prospectively dose patients newly started on warfarin. Seventy-one patients of an outpatient anticoagulation clinic at an academic medical center who were age 18 years or older on a stable, therapeutic warfarin dose with international normalized ratio (INR) goal between 2.0 and 3.0, and cytochrome P450 isoenzyme 2C9 (CYP2C9) and vitamin K epoxide reductase complex subunit 1 (VKORC1) genotypes available between January 1, 2007 and September 30, 2008 were included. Six pharmacogenetic warfarin dosing algorithms were identified from the medical literature. Additionally, a 5 mg fixed dose approach was evaluated. Three algorithms, Zhu et al. (Clin Chem 53:1199-1205, 2007), Gage et al. (J Clin Ther 84:326-331, 2008), and International Warfarin Pharmacogenetic Consortium (IWPC) (N Engl J Med 360:753-764, 2009) were similar in the primary accuracy endpoints with mean absolute error (MAE) ranging from 1.7 to 1.8 mg/day and coefficient of determination R (2) from 0.61 to 0.66. However, the Zhu et al. algorithm severely over-predicted dose (defined as >or=2x or >or=2 mg/day more than actual dose) in twice as many (14 vs. 7%) patients as Gage et al. 2008 and IWPC 2009. In conclusion, the algorithms published by Gage et al. 2008 and the IWPC 2009 were the two most accurate pharmacogenetically based equations available in the medical literature in predicting therapeutic warfarin dose in our study population. However, the degree of accuracy demonstrated does not support the routine use of genotyping to prospectively dose all patients newly started on warfarin.

Bernard Lerer: recipient of the 2014 inaugural Werner Kalow Responsible Innovation Prize in Global Omics and Personalized Medicine (Pacific Rim Association for Clinical Pharmacogenetics).

PubMed

Ozdemir, Vural; Endrenyi, Laszlo; Aynacıoğlu, Sükrü; Bragazzi, Nicola Luigi; Dandara, Collet; Dove, Edward S; Ferguson, Lynnette R; Geraci, Christy Jo; Hafen, Ernst; Kesim, Belgin Eroğlu; Kolker, Eugene; Lee, Edmund J D; Llerena, Adrian; Nacak, Muradiye; Shimoda, Kazutaka; Someya, Toshiyuki; Srivastava, Sanjeeva; Tomlinson, Brian; Vayena, Effy; Warnich, Louise; Yaşar, Umit

2014-04-01

This article announces the recipient of the 2014 inaugural Werner Kalow Responsible Innovation Prize in Global Omics and Personalized Medicine by the Pacific Rim Association for Clinical Pharmacogenetics (PRACP): Bernard Lerer, professor of psychiatry and director of the Biological Psychiatry Laboratory, Hadassah-Hebrew University Medical Center, Jerusalem, Israel. The Werner Kalow Responsible Innovation Prize is given to an exceptional interdisciplinary scholar who has made highly innovative and enduring contributions to global omics science and personalized medicine, with both vertical and horizontal (transdisciplinary) impacts. The prize is established in memory of a beloved colleague, mentor, and friend, the late Professor Werner Kalow, who cultivated the idea and practice of pharmacogenetics in modern therapeutics commencing in the 1950s. PRACP, the prize's sponsor, is one of the longest standing learned societies in the Asia-Pacific region, and was founded by Kalow and colleagues more than two decades ago in the then-emerging field of pharmacogenetics. In announcing this inaugural prize and its winner, we seek to highlight the works of prize winner, Professor Lerer. Additionally, we contextualize the significance of the prize by recalling the life and works of Professor Kalow and providing a brief socio-technical history of the rise of pharmacogenetics and personalized medicine as a veritable form of 21(st) century scientific practice. The article also fills a void in previous social science analyses of pharmacogenetics, by bringing to the fore the works of Kalow from 1995 to 2008, when he presciently noted the rise of yet another field of postgenomics inquiry--pharmacoepigenetics--that railed against genetic determinism and underscored the temporal and spatial plasticity of genetic components of drug response, with invention of the repeated drug administration (RDA) method that estimates the dynamic heritabilities of drug response. The prize goes a long way

Automating data acquisition into ontologies from pharmacogenetics relational data sources using declarative object definitions and XML.

PubMed

Rubin, Daniel L; Hewett, Micheal; Oliver, Diane E; Klein, Teri E; Altman, Russ B

2002-01-01

Ontologies are useful for organizing large numbers of concepts having complex relationships, such as the breadth of genetic and clinical knowledge in pharmacogenomics. But because ontologies change and knowledge evolves, it is time consuming to maintain stable mappings to external data sources that are in relational format. We propose a method for interfacing ontology models with data acquisition from external relational data sources. This method uses a declarative interface between the ontology and the data source, and this interface is modeled in the ontology and implemented using XML schema. Data is imported from the relational source into the ontology using XML, and data integrity is checked by validating the XML submission with an XML schema. We have implemented this approach in PharmGKB (http://www.pharmgkb.org/), a pharmacogenetics knowledge base. Our goals were to (1) import genetic sequence data, collected in relational format, into the pharmacogenetics ontology, and (2) automate the process of updating the links between the ontology and data acquisition when the ontology changes. We tested our approach by linking PharmGKB with data acquisition from a relational model of genetic sequence information. The ontology subsequently evolved, and we were able to rapidly update our interface with the external data and continue acquiring the data. Similar approaches may be helpful for integrating other heterogeneous information sources in order make the diversity of pharmacogenetics data amenable to computational analysis.

Pharmacogenetics in Acute Lymphoblastic Leukemia

PubMed Central

Cheok, Meyling H.; Pottier, Nicolas; Kager, Leo

2009-01-01

Progress in the treatment of acute leukemia in children has been remarkable, from a disease being lethal four decades ago to current cure rates exceeding 80%. This exemplary progress is largely due to the optimization of existing treatment modalities rather than the discovery of new antileukemic agents. However, despite these high cure rates, the annual number of children whose leukemia relapses after their initial therapy remains greater than that of new cases of most types of childhood cancers. The aim of pharmacogenetics is to develop strategies to personalize treatment and tailor therapy to individual patients, with the goal of optimizing efficacy and safety through better understanding of human genome variability and its influence on drug response. In this review, we summarize recent pharmacogenomic studies related to the treatment of pediatric acute lymphoblastic leukemia. These studies illustrate the promise of pharmacogenomics to further advance the treatment of human cancers, with childhood leukemia serving as a paradigm. PMID:19100367

Whole-Genome Sequencing of Pharmacogenetic Drug Response in Racially Diverse Children with Asthma.

PubMed

Mak, Angel C Y; White, Marquitta J; Eckalbar, Walter L; Szpiech, Zachary A; Oh, Sam S; Pino-Yanes, Maria; Hu, Donglei; Goddard, Pagé; Huntsman, Scott; Galanter, Joshua; Wu, Ann Chen; Himes, Blanca E; Germer, Soren; Vogel, Julia M; Bunting, Karen L; Eng, Celeste; Salazar, Sandra; Keys, Kevin L; Liberto, Jennifer; Nuckton, Thomas J; Nguyen, Thomas A; Torgerson, Dara G; Kwok, Pui-Yan; Levin, Albert M; Celedón, Juan C; Forno, Erick; Hakonarson, Hakon; Sleiman, Patrick M; Dahlin, Amber; Tantisira, Kelan G; Weiss, Scott T; Serebrisky, Denise; Brigino-Buenaventura, Emerita; Farber, Harold J; Meade, Kelley; Lenoir, Michael A; Avila, Pedro C; Sen, Saunak; Thyne, Shannon M; Rodriguez-Cintron, William; Winkler, Cheryl A; Moreno-Estrada, Andrés; Sandoval, Karla; Rodriguez-Santana, Jose R; Kumar, Rajesh; Williams, L Keoki; Ahituv, Nadav; Ziv, Elad; Seibold, Max A; Darnell, Robert B; Zaitlen, Noah; Hernandez, Ryan D; Burchard, Esteban G

2018-06-15

Albuterol, a bronchodilator medication, is the first-line therapy for asthma worldwide. There are significant racial/ethnic differences in albuterol drug response. To identify genetic variants important for bronchodilator drug response (BDR) in racially diverse children. We performed the first whole-genome sequencing pharmacogenetics study from 1,441 children with asthma from the tails of the BDR distribution to identify genetic association with BDR. We identified population-specific and shared genetic variants associated with BDR, including genome-wide significant (P < 3.53 × 10 -7 ) and suggestive (P < 7.06 × 10 -6 ) loci near genes previously associated with lung capacity (DNAH5), immunity (NFKB1 and PLCB1), and β-adrenergic signaling (ADAMTS3 and COX18). Functional analyses of the BDR-associated SNP in NFKB1 revealed potential regulatory function in bronchial smooth muscle cells. The SNP is also an expression quantitative trait locus for a neighboring gene, SLC39A8. The lack of other asthma study populations with BDR and whole-genome sequencing data on minority children makes it impossible to perform replication of our rare variant associations. Minority underrepresentation also poses significant challenges to identify age-matched and population-matched cohorts of sufficient sample size for replication of our common variant findings. The lack of minority data, despite a collaboration of eight universities and 13 individual laboratories, highlights the urgent need for a dedicated national effort to prioritize diversity in research. Our study expands the understanding of pharmacogenetic analyses in racially/ethnically diverse populations and advances the foundation for precision medicine in at-risk and understudied minority populations.

PG4KDS: A Model for the Clinical Implementation of Pre-emptive Pharmacogenetics

PubMed Central

Hoffman, James M.; Haidar, Cyrine E.; Wilkinson, Mark R.; Crews, Kristine R.; Baker, Donald K.; Kornegay, Nancy M.; Yang, Wenjian; Pui, Ching-Hon; Reiss, Ulrike M.; Gaur, Aditya H.; Howard, Scott C.; Evans, William E.; Broeckel, Ulrich; Relling, Mary V.

2014-01-01

Pharmacogenetics is frequently cited as an area for initial focus of the clinical implementation of genomics. Through the PG4KDS protocol, St. Jude Children’s Research Hospital pre-emptively genotypes patients for 230 genes using the Affymetrix Drug Metabolizing Enzymes and Transporters (DMET) Plus array supplemented with a CYP2D6 copy number assay. The PG4KDS protocol provides a rational, stepwise process for implementing gene/drug pairs, organizing data, and obtaining consent from patients and families. Through August 2013, 1559 patients have been enrolled, and 4 gene tests have been released into the electronic health record (EHR) for clinical implementation: TPMT, CYP2D6, SLCO1B1, and CYP2C19. These genes are coupled to 12 high-risk drugs. Of the 1016 patients with genotype test results available, 78% of them had at least one high-risk (i.e., actionable) genotype result placed in their EHR. Each diplotype result released to the EHR is coupled with an interpretive consult that is created in a concise, standardized format. To support-gene based prescribing at the point of care, 55 interruptive clinical decision support (CDS) alerts were developed. Patients are informed of their genotyping result and its relevance to their medication use through a letter. Key elements necessary for our successful implementation have included strong institutional support, a knowledgeable clinical laboratory, a process to manage any incidental findings, a strategy to educate clinicians and patients, a process to return results, and extensive use of informatics, especially CDS. Our approach to pre-emptive clinical pharmacogenetics has proven feasible, clinically useful, and scalable. PMID:24619595

PG4KDS: a model for the clinical implementation of pre-emptive pharmacogenetics.

PubMed

Hoffman, James M; Haidar, Cyrine E; Wilkinson, Mark R; Crews, Kristine R; Baker, Donald K; Kornegay, Nancy M; Yang, Wenjian; Pui, Ching-Hon; Reiss, Ulrike M; Gaur, Aditya H; Howard, Scott C; Evans, William E; Broeckel, Ulrich; Relling, Mary V

2014-03-01

Pharmacogenetics is frequently cited as an area for initial focus of the clinical implementation of genomics. Through the PG4KDS protocol, St. Jude Children's Research Hospital pre-emptively genotypes patients for 230 genes using the Affymetrix Drug Metabolizing Enzymes and Transporters (DMET) Plus array supplemented with a CYP2D6 copy number assay. The PG4KDS protocol provides a rational, stepwise process for implementing gene/drug pairs, organizing data, and obtaining consent from patients and families. Through August 2013, 1,559 patients have been enrolled, and four gene tests have been released into the electronic health record (EHR) for clinical implementation: TPMT, CYP2D6, SLCO1B1, and CYP2C19. These genes are coupled to 12 high-risk drugs. Of the 1,016 patients with genotype test results available, 78% of them had at least one high-risk (i.e., actionable) genotype result placed in their EHR. Each diplotype result released to the EHR is coupled with an interpretive consult that is created in a concise, standardized format. To support-gene based prescribing at the point of care, 55 interruptive clinical decision support (CDS) alerts were developed. Patients are informed of their genotyping result and its relevance to their medication use through a letter. Key elements necessary for our successful implementation have included strong institutional support, a knowledgeable clinical laboratory, a process to manage any incidental findings, a strategy to educate clinicians and patients, a process to return results, and extensive use of informatics, especially CDS. Our approach to pre-emptive clinical pharmacogenetics has proven feasible, clinically useful, and scalable. © 2014 Wiley Periodicals, Inc.

Pharmacogenetic Variation in Over 100 Genes in Patients Receiving Acenocumarol

PubMed Central

Gonzalez-Covarrubias, Vanessa; Urena-Carrion, Javier; Villegas-Torres, Beatriz; Cossío-Aranda, J. Eduardo; Trevethan-Cravioto, Sergio; Izaguirre-Avila, Raul; Fiscal-López, O. Javier; Soberon, Xavier

2017-01-01

Coumarins are widely prescribed worldwide, and in Mexico acenocumarol is the preferred form. It is well known that despite its efficacy, coumarins show a high variability for dose requirements. We investigated the pharmacogenetic variation of 110 genes in patients receiving acenocumarol using a targeted NGS approach. We report relevant population differentiation for variants on CYP2C8, CYP2C19, CYP4F11, CYP4F2, PROS, and GGCX, VKORC1, CYP2C18, NQO1. A higher proportion of novel-to-known variants for 10 genes was identified on 41 core pharmacogenomics genes related to the PK (29), PD (3), of coumarins, and coagulation proteins (9) including, CYP1A1, CYP3A4, CYP3A5, and F8, and a low proportion of novel-to-known variants on CYP2E1, VKORC1, and SULT1A1/2. Using a Bayesian approach, we identified variants influencing acenocumarol dosing on, VKORC1 (2), SULT1A1 (1), and CYP2D8P (1) explaining 40–55% of dose variability. A collection of pharmacogenetic variation on 110 genes related to the PK/PD of coumarins is also presented. Our results offer an initial insight into the use of a targeted NGS approach in the pharmacogenomics of coumarins in Mexican Mestizos. PMID:29218011

Comparison of the Performance of the Warfarin Pharmacogenetics Algorithms in Patients with Surgery of Heart Valve Replacement and Heart Valvuloplasty.

PubMed

Xu, Hang; Su, Shi; Tang, Wuji; Wei, Meng; Wang, Tao; Wang, Dongjin; Ge, Weihong

2015-09-01

A large number of warfarin pharmacogenetics algorithms have been published. Our research was aimed to evaluate the performance of the selected pharmacogenetic algorithms in patients with surgery of heart valve replacement and heart valvuloplasty during the phase of initial and stable anticoagulation treatment. 10 pharmacogenetic algorithms were selected by searching PubMed. We compared the performance of the selected algorithms in a cohort of 193 patients during the phase of initial and stable anticoagulation therapy. Predicted dose was compared to therapeutic dose by using a predicted dose percentage that falls within 20% threshold of the actual dose (percentage within 20%) and mean absolute error (MAE). The average warfarin dose for patients was 3.05±1.23mg/day for initial treatment and 3.45±1.18mg/day for stable treatment. The percentages of the predicted dose within 20% of the therapeutic dose were 44.0±8.8% and 44.6±9.7% for the initial and stable phases, respectively. The MAEs of the selected algorithms were 0.85±0.18mg/day and 0.93±0.19mg/day, respectively. All algorithms had better performance in the ideal group than in the low dose and high dose groups. The only exception is the Wadelius et al. algorithm, which had better performance in the high dose group. The algorithms had similar performance except for the Wadelius et al. and Miao et al. algorithms, which had poor accuracy in our study cohort. The Gage et al. algorithm had better performance in both phases of initial and stable treatment. Algorithms had relatively higher accuracy in the >50years group of patients on the stable phase. Copyright © 2015 Elsevier Ltd. All rights reserved.

LTAR linkages with other research networks: Capitalizing on network interconnections

USDA-ARS?s Scientific Manuscript database

The USDA ARS Research Unit based at the Jornada Experimental Range outside of Las Cruces, NM, is a member of the USDA’s Long Term Agro-ecosystem Research (LTAR) Network, the National Science Foundation’s Long Term Ecological Research (LTER) Network, the National Ecological Observation Network (NEON)...

Pharmacogenetic determinants of mercaptopurine disposition in children with acute lymphoblastic leukemia.

PubMed

Adam de Beaumais, Tiphaine; Jacqz-Aigrain, Evelyne

2012-09-01

The backbone of drug therapy used in acute lymphoblastic leukemia (ALL) in children includes 6-mercaptopurine (6-MP). Intracellular metabolism of this prodrug is a key component of the therapeutic response. Many metabolizing enzymes are involved in 6-MP disposition and active 6-MP metabolites are represented by 6-thioguanine nucleotides (6-TGN) and methylated metabolites primarily methylated by the thiopurine S-methyltransferase enzyme (TPMT). The genetic polymorphism affecting TPMT activity displays an important inter-subject variability in metabolites pharmacokinetics and influences the balance between 6-MP efficacy and toxicity: patients with high 6-TGN levels are at risk of myelosuppression while patients with high levels of methylated derivates are at hepatotoxic risk. However, the genetic TPMT polymorphism does not explain all 6-MP adverse events and some severe toxicities leading to life-threatening conditions remain unexplained. Additional single nucleotide polymorphisms (SNPs) in genes encoding enzymes involved in 6-MP metabolism and 6-MP transporters may also be responsible for this inter-individual 6-MP response variability. This review presents the pharmacogenetic aspects of 6-MP metabolism in great detail. We have focused on published data on ALL treatment supporting the great potential of 6-MP pharmacogenetics to improve efficacy, tolerance, and event-free survival rates in children with ALL.

Pharmacogenetics of asthma

PubMed Central

Lima, John J.; Blake, Kathryn V.; Tantisira, Kelan G.; Weiss, Scott T.

2009-01-01

Purpose of review Patient response to the asthma drug classes, bronchodilators, inhaled corticosteroids and leukotriene modifiers, are characterized by a large degree of heterogeneity, which is attributable in part to genetic variation. Herein, we review and update the pharmacogenetics and pharmaogenomics of common asthma drugs. Recent findings Early studies suggest that bronchodilator reversibility and asthma worsening in patients on continuous short-acting and long-acting β-agonists are related to the Gly16Arg genotype for the ADRB2. More recent studies including genome-wide association studies implicate variants in other genes contribute to bronchodilator response heterogeneity and fail to replicate asthma worsening associated with continuous β-agonist use. Genetic determinants of the safety of long-acting β-agonist require further study. Variants in CRHR1, TBX21, and FCER2 contribute to variability in response for lung function, airways responsiveness, and exacerbations in patients taking inhaled corticosteroids. Variants in ALOX5, LTA4H, LTC4S, ABCC1, CYSLTR2, and SLCO2B1 contribute to variability in response to leukotriene modifiers. Summary Identification of novel variants that contribute to response heterogeneity supports future studies of single nucleotide polymorphism discovery and include gene expression and genome-wide association studies. Statistical models that predict the genomics of response to asthma drugs will complement single nucleotide polymorphism discovery in moving toward personalized medicine. PMID:19077707

Concordance between actual and pharmacogenetic predicted desvenlafaxine dose needed to achieve remission in major depressive disorder: a 10-week open-label study.

PubMed

Bousman, Chad A; Müller, Daniel J; Ng, Chee H; Byron, Keith; Berk, Michael; Singh, Ajeet B

2017-01-01

Pharmacogenetic-based dosing support tools have been developed to personalize antidepressant-prescribing practice. However, the clinical validity of these tools has not been adequately tested, particularly for specific antidepressants. To examine the concordance between the actual dose and a polygene pharmacogenetic predicted dose of desvenlafaxine needed to achieve symptom remission. A 10-week, open-label, prospective trial of desvenlafaxine among Caucasian adults with major depressive disorder (n=119) was conducted. Dose was clinically adjusted and at the completion of the trial, the clinical dose needed to achieve remission was compared with the predicted dose needed to achieve remission. Among remitters (n=95), there was a strong concordance (Kendall's τ-b=0.84, P=0.0001; Cohen's κ=0.82, P=0.0001) between the actual and the predicted dose need to achieve symptom remission, showing high sensitivity (≥85%), specificity (≥86%), and accuracy (≥89%) of the tool. Findings provide initial evidence for the clinical validity of a polygene pharmacogenetic-based tool for desvenlafaxine dosing.

Pharmacogenetics-based warfarin dosing algorithm decreases time to stable anticoagulation and the risk of major hemorrhage: an updated meta-analysis of randomized controlled trials.

PubMed

Wang, Zhi-Quan; Zhang, Rui; Zhang, Peng-Pai; Liu, Xiao-Hong; Sun, Jian; Wang, Jun; Feng, Xiang-Fei; Lu, Qiu-Fen; Li, Yi-Gang

2015-04-01

Warfarin is yet the most widely used oral anticoagulant for thromboembolic diseases, despite the recently emerged novel anticoagulants. However, difficulty in maintaining stable dose within the therapeutic range and subsequent serious adverse effects markedly limited its use in clinical practice. Pharmacogenetics-based warfarin dosing algorithm is a recently emerged strategy to predict the initial and maintaining dose of warfarin. However, whether this algorithm is superior over conventional clinically guided dosing algorithm remains controversial. We made a comparison of pharmacogenetics-based versus clinically guided dosing algorithm by an updated meta-analysis. We searched OVID MEDLINE, EMBASE, and the Cochrane Library for relevant citations. The primary outcome was the percentage of time in therapeutic range. The secondary outcomes were time to stable therapeutic dose and the risks of adverse events including all-cause mortality, thromboembolic events, total bleedings, and major bleedings. Eleven randomized controlled trials with 2639 participants were included. Our pooled estimates indicated that pharmacogenetics-based dosing algorithm did not improve percentage of time in therapeutic range [weighted mean difference, 4.26; 95% confidence interval (CI), -0.50 to 9.01; P = 0.08], but it significantly shortened the time to stable therapeutic dose (weighted mean difference, -8.67; 95% CI, -11.86 to -5.49; P < 0.00001). Additionally, pharmacogenetics-based algorithm significantly reduced the risk of major bleedings (odds ratio, 0.48; 95% CI, 0.23 to 0.98; P = 0.04), but it did not reduce the risks of all-cause mortality, total bleedings, or thromboembolic events. Our results suggest that pharmacogenetics-based warfarin dosing algorithm significantly improves the efficiency of International Normalized Ratio correction and reduces the risk of major hemorrhage.

Lithium Pharmacogenetics: Where Do We Stand?

PubMed

Pisanu, Claudia; Melis, Carla; Squassina, Alessio

2016-11-01

Preclinical Research Bipolar disorder (BPD) is a chronic and disabling psychiatric disorder with a prevalence of 0.8-1.2% in the general population. Although lithium is considered the first-line treatment, a large percentage of patients do not respond sufficiently. Moreover, lithium can induce severe side effects and has poor tolerance and a narrow therapeutic index. The genetics of lithium response has been largely investigated, but findings have so far failed to identify reliable biomarkers to predict clinical response. This has been largely determined by the highly complex phenotipic and genetic architecture of lithium response. To this regard, collaborative initiatives hold the promise to provide robust and standardized methods to disantenagle this complexity, as well as the capacity to collect large samples of patietnts, a crucial requirement to study the genetics of complex phenotypes. The International Consortium on Lithium Genetics (ConLiGen) has recently published the largest study so far on lithium response reporting significant associations for two long noncoding RNAs (lncRNAs). This result provides relevant insights into the pharmacogenetics of lithium supporting the involvement of the noncoding portion of the genome in modulating clinical response. Although a vast body of research is engaged in dissecting the genetic bases of response to lithium, the several drawbacks of lithium therapy have also stimulated multiple efforts to identify new safer treatments. A drug repurposing approach identified ebselen as a potential lithium mimetic, as it shares with lithium the ability to inhibit inositol monophosphatase. Ebselen, an antioxidant glutathione peroxidase mimetic, represents a valid and promising example of new potential therapeutic interventions for BD, but the paucity of data warrant further investigation to elucidate its potential efficacy and safety in the management of BPD. Nevertheless, findings provided by the growing field of pharmacogenomic

Smoking cessation pharmacogenetics: analysis of varenicline and bupropion in placebo-controlled clinical trials.

PubMed

King, David P; Paciga, Sara; Pickering, Eve; Benowitz, Neal L; Bierut, Laura J; Conti, David V; Kaprio, Jaakko; Lerman, Caryn; Park, Peter W

2012-02-01

Despite effective therapies for smoking cessation, most smokers find quitting difficult and most successful quitters relapse. Considerable evidence supports a genetic risk for nicotine dependence; however, less is known about the pharmacogenetics of smoking cessation. In the first pharmacogenetic investigation of the efficacy of varenicline and bupropion, we examined whether genes important in the pharmacodynamics and pharmacokinetics of these drugs and nicotine predict medication efficacy and adverse events. Subjects participated in randomized, double-blind, placebo-controlled smoking cessation clinical trials, comparing varenicline, a nicotinic acetylcholine receptor (nAChR) partial agonist, with bupropion, a norepinephrine/dopamine reuptake inhibitor, and placebo. Primary analysis included 1175 smokers of European ancestry, and 785 single nucleotide polymorphisms from 24 genes, representing 254 linkage disequilibrium (LD) bins (genes included nAChR subunits, additional varenicline-specific genes, and genes involved in nicotine or bupropion metabolism). For varenicline, continuous abstinence (weeks 9-12) was associated with multiple nAChR subunit genes (including CHRNB2, CHRNA5, and CHRNA4) (OR=1.76; 95% CI: 1.23-2.52) (p<0.005); for bupropion, abstinence was associated with CYP2B6 (OR=1.78; 95% CI: 1.27-2.50) (p<0.001). Incidence of nausea was associated with several nAChR subunit genes (OR=0.50; 95% CI: 0.36-0.70) (p<0.0001) and time to relapse after quitting was associated with HTR3B (HR=1.97; 95% CI: 1.45-2.68) (p<0.0001). These data provide evidence for multiple genetic loci contributing to smoking cessation and therapeutic response. Different loci are associated with varenicline vs bupropion response, suggesting that additional research may identify clinically useful markers to guide treatment decisions.

The Prevention Research Centers Healthy Aging Research Network.

PubMed

Lang, Jason E; Anderson, Lynda; LoGerfo, James; Sharkey, Joseph; Belansky, Elaine; Bryant, Lucinda; Prohaska, Tom; Altpeter, Mary; Marshall, Victor; Satariano, William; Ivey, Susan; Bayles, Constance; Pluto, Delores; Wilcox, Sara; Goins, R Turner; Byrd, Robert C

2006-01-01

The Prevention Research Centers Healthy Aging Research Network (PRC-HAN), funded by the Centers for Disease Control and Prevention's (CDC's) Healthy Aging program, was created in 2001 to help develop partnerships and create a research agenda that promotes healthy aging. The nine universities that participate in the network use their expertise in aging research to collaborate with their communities and other partners to develop and implement health promotion interventions for older adults at the individual, organizational, environmental, and policy levels. The population of older adults in the United States is growing rapidly; approximately 20% of Americans will be aged 65 years or older by 2030. The health and economic impact of an aging society compel the CDC and the public health community to place increased emphasis on preventing unnecessary disease, disability, and injury among older Americans. The PRC-HAN has a broad research agenda that addresses health-promoting skills and behaviors, disease and syndrome topics, and knowledge domains. The network chose physical activity for older adults as its initial focus for research and has initiated two networkwide projects: a comprehensive, multisite survey that collected information on the capacity, content, and accessibility of physical activity programs for older adults and a peer-reviewed publication that describes the role of public health in promoting physical activity among older adults. In addition to participating in the core research area, each network member works independently with its community committee on PRC-HAN activities. As a result, the network is 1) expanding prevention research for older adults and their communities; 2) promoting the translation and dissemination of findings to key stakeholders; 3) strengthening PRC-HAN capacity through partnerships and expanded funding; and 4) stimulating the adoption of policies and programs by engaging policymakers, planners, and practitioners. In 2003, the PRC

Research of ad hoc network based on SINCGARS network

NASA Astrophysics Data System (ADS)

Nie, Hao; Cai, Xiaoxia; Chen, Hong; Chen, Jian; Weng, Pengfei

2016-03-01

In today's world, science and technology make a spurt of progress, so society has entered the era of information technology, network. Only the comprehensive use of electronic warfare and network warfare means can we maximize their access to information and maintain the information superiority. Combined with the specific combat mission and operational requirements, the research design and construction in accordance with the actual military which are Suitable for the future of information technology needs of the tactical Adhoc network, tactical internet, will greatly improve the operational efficiency of the command of the army. Through the study of the network of the U.S. military SINCGARS network, it can explore the routing protocol and mobile model, to provide a reference for the research of our army network.

Role of practice-based research networks in comparative effectiveness research.

PubMed

Hartung, Daniel M; Guise, Jeanne-Marie; Fagnan, Lyle J; Davis, Melinda M; Stange, Kurt C

2012-01-01

Comparative effectiveness research fundamentally reorients how clinical evidence is generated and used with the goal of providing actionable information to decision-makers. To achieve this, it is vital that decision-makers and the research enterprise are engaged from research inception, to evidence generation and translation. Practice-based research networks are affiliated clinicians in diverse communities with the goal of conducting research to improve care. Practice-based research networks have the potential to advance all phases of the comparative effectiveness research cycle. The aim of this paper is to explore current and potential roles of practice-based research networks in conducting comparative effectiveness research.

Privacy in Pharmacogenetics: An End-to-End Case Study of Personalized Warfarin Dosing.

PubMed

Fredrikson, Matthew; Lantz, Eric; Jha, Somesh; Lin, Simon; Page, David; Ristenpart, Thomas

2014-08-01

We initiate the study of privacy in pharmacogenetics, wherein machine learning models are used to guide medical treatments based on a patient's genotype and background. Performing an in-depth case study on privacy in personalized warfarin dosing, we show that suggested models carry privacy risks, in particular because attackers can perform what we call model inversion : an attacker, given the model and some demographic information about a patient, can predict the patient's genetic markers. As differential privacy (DP) is an oft-proposed solution for medical settings such as this, we evaluate its effectiveness for building private versions of pharmacogenetic models. We show that DP mechanisms prevent our model inversion attacks when the privacy budget is carefully selected . We go on to analyze the impact on utility by performing simulated clinical trials with DP dosing models. We find that for privacy budgets effective at preventing attacks, patients would be exposed to increased risk of stroke, bleeding events, and mortality . We conclude that current DP mechanisms do not simultaneously improve genomic privacy while retaining desirable clinical efficacy, highlighting the need for new mechanisms that should be evaluated in situ using the general methodology introduced by our work.

Privacy in Pharmacogenetics: An End-to-End Case Study of Personalized Warfarin Dosing

PubMed Central

Fredrikson, Matthew; Lantz, Eric; Jha, Somesh; Lin, Simon; Page, David; Ristenpart, Thomas

2014-01-01

We initiate the study of privacy in pharmacogenetics, wherein machine learning models are used to guide medical treatments based on a patient’s genotype and background. Performing an in-depth case study on privacy in personalized warfarin dosing, we show that suggested models carry privacy risks, in particular because attackers can perform what we call model inversion: an attacker, given the model and some demographic information about a patient, can predict the patient’s genetic markers. As differential privacy (DP) is an oft-proposed solution for medical settings such as this, we evaluate its effectiveness for building private versions of pharmacogenetic models. We show that DP mechanisms prevent our model inversion attacks when the privacy budget is carefully selected. We go on to analyze the impact on utility by performing simulated clinical trials with DP dosing models. We find that for privacy budgets effective at preventing attacks, patients would be exposed to increased risk of stroke, bleeding events, and mortality. We conclude that current DP mechanisms do not simultaneously improve genomic privacy while retaining desirable clinical efficacy, highlighting the need for new mechanisms that should be evaluated in situ using the general methodology introduced by our work. PMID:27077138

Research in network management techniques for tactical data communications networks

NASA Astrophysics Data System (ADS)

Boorstyn, R.; Kershenbaum, A.; Maglaris, B.; Sarachik, P.

1982-09-01

This is the final technical report for work performed on network management techniques for tactical data networks. It includes all technical papers that have been published during the control period. Research areas include Packet Network modelling, adaptive network routing, network design algorithms, network design techniques, and local area networks.

Role of practice-based research networks in comparative effectiveness research

PubMed Central

Hartung, Daniel M; Guise, Jeanne-Marie; Fagnan, Lyle J; Davis, Melinda M; Stange, Kurt C

2012-01-01

Comparative effectiveness research fundamentally reorients how clinical evidence is generated and used with the goal of providing actionable information to decision-makers. To achieve this, it is vital that decision-makers and the research enterprise are engaged from research inception, to evidence generation and translation. Practice-based research networks are affiliated clinicians in diverse communities with the goal of conducting research to improve care. Practice-based research networks have the potential to advance all phases of the comparative effectiveness research cycle. The aim of this paper is to explore current and potential roles of practice-based research networks in conducting comparative effectiveness research. PMID:23105964

Concordance between actual and pharmacogenetic predicted desvenlafaxine dose needed to achieve remission in major depressive disorder: a 10-week open-label study

PubMed Central

Müller, Daniel J.; Ng, Chee H.; Byron, Keith; Berk, Michael; Singh, Ajeet B.

2017-01-01

Background Pharmacogenetic-based dosing support tools have been developed to personalize antidepressant-prescribing practice. However, the clinical validity of these tools has not been adequately tested, particularly for specific antidepressants. Objective To examine the concordance between the actual dose and a polygene pharmacogenetic predicted dose of desvenlafaxine needed to achieve symptom remission. Materials and methods A 10-week, open-label, prospective trial of desvenlafaxine among Caucasian adults with major depressive disorder (n=119) was conducted. Dose was clinically adjusted and at the completion of the trial, the clinical dose needed to achieve remission was compared with the predicted dose needed to achieve remission. Results Among remitters (n=95), there was a strong concordance (Kendall’s τ-b=0.84, P=0.0001; Cohen’s κ=0.82, P=0.0001) between the actual and the predicted dose need to achieve symptom remission, showing high sensitivity (≥85%), specificity (≥86%), and accuracy (≥89%) of the tool. Conclusion Findings provide initial evidence for the clinical validity of a polygene pharmacogenetic-based tool for desvenlafaxine dosing. PMID:27779571

Pharmacogenetics of warfarin: challenges and opportunities

PubMed Central

Ta Michael Lee, Ming; Klein, Teri E

2014-01-01

Since the introduction in the 1950s, warfarin has become the commonly used oral anticoagulant for the prevention of thromboembolism in patients with deep vein thrombosis, atrial fibrillation or prosthetic heart valve replacement. Warfarin is highly efficacious; however, achieving the desired anticoagulation is difficult because of its narrow therapeutic window and highly variable dose response among individuals. Bleeding is often associated with overdose of warfarin. There is overwhelming evidence that an individual's warfarin maintenance is associated with clinical factors and genetic variations, most notably polymorphisms in cytochrome P450 2C9 and vitamin K epoxide reductase subunit 1. Numerous dose-prediction algorithms incorporating both genetic and clinical factors have been developed and tested clinically. However, results from major clinical trials are not available yet. This review aims to provide an overview of the field of warfarin which includes information about the drug, genetics of warfarin dose requirements, dosing algorithms developed and the challenges for the clinical implementation of warfarin pharmacogenetics. PMID:23657428

Efficiency and effectiveness of the use of an acenocoumarol pharmacogenetic dosing algorithm versus usual care in patients with venous thromboembolic disease initiating oral anticoagulation: study protocol for a randomized controlled trial

PubMed Central

2012-01-01

Background Hemorrhagic events are frequent in patients on treatment with antivitamin-K oral anticoagulants due to their narrow therapeutic margin. Studies performed with acenocoumarol have shown the relationship between demographic, clinical and genotypic variants and the response to these drugs. Once the influence of these genetic and clinical factors on the dose of acenocoumarol needed to maintain a stable international normalized ratio (INR) has been demonstrated, new strategies need to be developed to predict the appropriate doses of this drug. Several pharmacogenetic algorithms have been developed for warfarin, but only three have been developed for acenocoumarol. After the development of a pharmacogenetic algorithm, the obvious next step is to demonstrate its effectiveness and utility by means of a randomized controlled trial. The aim of this study is to evaluate the effectiveness and efficiency of an acenocoumarol dosing algorithm developed by our group which includes demographic, clinical and pharmacogenetic variables (VKORC1, CYP2C9, CYP4F2 and ApoE) in patients with venous thromboembolism (VTE). Methods and design This is a multicenter, single blind, randomized controlled clinical trial. The protocol has been approved by La Paz University Hospital Research Ethics Committee and by the Spanish Drug Agency. Two hundred and forty patients with VTE in which oral anticoagulant therapy is indicated will be included. Randomization (case/control 1:1) will be stratified by center. Acenocoumarol dose in the control group will be scheduled and adjusted following common clinical practice; in the experimental arm dosing will be following an individualized algorithm developed and validated by our group. Patients will be followed for three months. The main endpoints are: 1) Percentage of patients with INR within the therapeutic range on day seven after initiation of oral anticoagulant therapy; 2) Time from the start of oral anticoagulant treatment to achievement of a

Research Priorities in Networking and Communications.

ERIC Educational Resources Information Center

National Science Foundation, Washington, DC.

A workshop focused on major research issues in networking and communications. This report defines the context for research priorities and initiatives and deals with issues in networking and communications. Fifteen major research priorities and four research specific initiatives were identified by participants as areas that should be pursued over…

Developing knowledge resources to support precision medicine: principles from the Clinical Pharmacogenetics Implementation Consortium (CPIC).

PubMed

Hoffman, James M; Dunnenberger, Henry M; Kevin Hicks, J; Caudle, Kelly E; Whirl Carrillo, Michelle; Freimuth, Robert R; Williams, Marc S; Klein, Teri E; Peterson, Josh F

2016-07-01

To move beyond a select few genes/drugs, the successful adoption of pharmacogenomics into routine clinical care requires a curated and machine-readable database of pharmacogenomic knowledge suitable for use in an electronic health record (EHR) with clinical decision support (CDS). Recognizing that EHR vendors do not yet provide a standard set of CDS functions for pharmacogenetics, the Clinical Pharmacogenetics Implementation Consortium (CPIC) Informatics Working Group is developing and systematically incorporating a set of EHR-agnostic implementation resources into all CPIC guidelines. These resources illustrate how to integrate pharmacogenomic test results in clinical information systems with CDS to facilitate the use of patient genomic data at the point of care. Based on our collective experience creating existing CPIC resources and implementing pharmacogenomics at our practice sites, we outline principles to define the key features of future knowledge bases and discuss the importance of these knowledge resources for pharmacogenomics and ultimately precision medicine. © The Author 2016. Published by Oxford University Press on behalf of the American Medical Informatics Association. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Influence of pre-hydration and pharmacogenetics on plasma methotrexate concentration and renal dysfunction following high-dose methotrexate therapy.

PubMed

Yanagimachi, Masakatsu; Goto, Hiroaki; Kaneko, Tetsuji; Naruto, Takuya; Sasaki, Koji; Takeuchi, Masanobu; Tanoshima, Reo; Kato, Hiromi; Yokosuka, Tomoko; Kajiwara, Ryosuke; Fujii, Hisaki; Tanaka, Fumiko; Goto, Shoko; Takahashi, Hiroyuki; Mori, Masaaki; Kai, Sumio; Yokota, Shumpei

2013-12-01

High-dose methotrexate therapy (HD-MTX) has been well established for the treatment of childhood acute lymphoblastic leukemia (ALL). The aims of this study were to investigate whether clinical and pharmacogenetic factors influence plasma MTX concentration and renal dysfunction in patients treated with HD-MTX. In a total of 127 courses of HD-MTX in 51 patients with childhood ALL, influence of clinical and pharmacogenetic factors on plasma MTX concentration and HD-MTX-related renal dysfunction was evaluated. Clinical factors included age, gender, duration of HD-MTX continuous-infusion and duration of pre-hydration before HD-MTX. Pharmacogenetic factors included 5 gene polymorphisms within the MTX pathway genes, namely, SLC19A1, MTHFR, ABCC2 and ABCG2. Short duration of pre-hydration before HD-MTX is the most important risk factor for prolonged high MTX concentration (p < 0.001, OR 6.40, 95 % CI 2.39-17.16) and renal dysfunction (p = 0.013, OR 3.15, 95 % CI 1.27-7.80). The T allele at MTHFR C677T was the risk factor for prolonged high MTX concentration (p = 0.009, OR 5.54, 95 % CI 1.54-19.85), but not for renal dysfunction. We found the influence of MTHFR C677T polymorphism on prolonged high MTX concentration. We reconfirmed the importance of adequate pre-hydration before HD-MTX to prevent prolonged high MTX concentration and MTX-related renal dysfunction.

Clinical importance of pharmacogenetics in the treatment of hepatitis C virus infection.

PubMed

Kamal, Adina Maria; MitruŢ, Paul; Kamal, Kamal Constantin; Tica, Oana Sorina; Niculescu, Mihaela; Alexandru, Dragoş Ovidiu; Tica, Andrei Adrian

2016-01-01

Globally, over 4% of the world population is affected by hepatitis C virus (HCV) infection. The current standard of care for hepatitis C infection is combination therapy with pegylated interferon and ribavirin for 48 weeks, which yield a sustained virological response in only a little over half of the patients with genotype 1 HCV. We investigated the clinical importance of pharmacogenetics in treatment efficacy and prediction of hematotoxicity. A total of 148 patients infected with HCV were enrolled. All patients were treated for a period of 48 weeks or less with pegylated interferon and ribavirin. Four genotypes were investigated: inosine triphosphatase (ITPA) rs1127354, C20orf194 rs6051702, interferon lambda (IFNL)3 rs8099917, IFNL3÷4 rs12979860 in the population from southwestern Romania. Genetic variants for rs129798660 and rs6051702 proved once more to represent an indisputable clinical tool for predicting sustained virological response (SVR) (69.23%, chi-square p=0.007846, p<0.05 and 63.29%, chi-square p=0.007846, p<0.05, respectively). ITPA genetic variants protect against ribavirin-induced hemolytic anemia and C20orf194 also proved to be protective against thrombocytopenia. These clinical findings strengthen the belief that pharmacogenetics should play a constant role in treatment decisions for patients infected with hepatitis C virus.

How does pharmacogenetic testing alter the treatment course and patient response for chronic-pain patients in comparison with the current "trial-and-error" standard of care?

PubMed

DeFeo, Kelly; Sykora, Kristen; Eley, Susan; Vincent, Debra

2014-10-01

To evaluate if pharmacogenetic testing (PT) holds value for pain-management practitioners by identifying the potential applications of pharmacogenetic research as well as applications in practice. A review of the literature was conducted utilizing the databases EBSCOhost, Biomedical Reference Collection, CINAHL, Health Business: Full Text, Health Source: Nursing/Academic Edition, and MEDLINE with the keywords, personalized medicine, cytochrome P450, and phamacogenetics. Chronic-pain patients present some of the most challenging patients to manage medically. Often paired with persistent, life-altering pain, they might also have oncologic and psychological comorbidities that can further complicate their management. One-step in-office PT is now widely available to optimize management of complicated patients and affectively remove the "trial-and-error" process of medication therapy. Practitioners must be familiar with the genetic determinants that affect a patient's response to medications in order to decrease preventable morbidity and mortality associated with drug-drug and patient-drug interactions, and to provide cost-effective care through avoidance of inappropriate medications. Improved pain managements will impove patient outcomes and satisfaction. ©2014 American Association of Nurse Practitioners.

Atomoxetine pharmacogenetics: associations with pharmacokinetics, treatment response and tolerability.

PubMed

Brown, Jacob T; Bishop, Jeffrey R

2015-01-01

Atomoxetine is indicated for the treatment of attention deficit hyperactivity disorder and is predominantly metabolized by the CYP2D6 enzyme. Differences in pharmacokinetic parameters as well as clinical treatment outcomes across CYP2D6 genotype groups have resulted in dosing recommendations within the product label, but clinical studies supporting the use of genotype guided dosing are currently lacking. Furthermore, pharmacokinetic and clinical studies have primarily focused on extensive as compared with poor metabolizers, with little information known about other metabolizer categories as well as genes involved in the pharmacodynamics of atomoxetine. This review describes the pharmacogenetic associations with atomoxetine pharmacokinetics, treatment response and tolerability with considerations for the clinical utility of this information.

Pharmacokinetics, pharmacodynamics, and pharmacogenetics of hydroxyurea treatment for children with sickle cell anemia

PubMed Central

Despotovic, Jenny M.; Mortier, Nicole A.; Flanagan, Jonathan M.; He, Jin; Smeltzer, Matthew P.; Kimble, Amy C.; Aygun, Banu; Wu, Song; Howard, Thad; Sparreboom, Alex

2011-01-01

Hydroxyurea therapy has proven laboratory and clinical efficacies for children with sickle cell anemia (SCA). When administered at maximum tolerated dose (MTD), hydroxyurea increases fetal hemoglobin (HbF) to levels ranging from 10% to 40%. However, interpatient variability of percentage of HbF (%HbF) response is high, MTD itself is variable, and accurate predictors of hydroxyurea responses do not currently exist. HUSTLE (NCT00305175) was designed to provide first-dose pharmacokinetics (PK) data for children with SCA initiating hydroxyurea therapy, to investigate pharmacodynamics (PD) parameters, including HbF response and MTD after standardized dose escalation, and to evaluate pharmacogenetics influences on PK and PD parameters. For 87 children with first-dose PK studies, substantial interpatient variability was observed, plus a novel oral absorption phenotype (rapid or slow) that influenced serum hydroxyurea levels and total hydroxyurea exposure. PD responses in 174 subjects were robust and similar to previous cohorts; %HbF at MTD was best predicted by 5 variables, including baseline %HbF, whereas MTD was best predicted by 5 variables, including serum creatinine. Pharmacogenetics analysis showed single nucleotide polymorphisms influencing baseline %HbF, including 5 within BCL11A, but none influencing MTD %HbF or dose. Accurate prediction of hydroxyurea treatment responses for SCA remains a worthy but elusive goal. PMID:21876119

ABCB1 haplotype and OPRM1 118A > G genotype interaction in methadone maintenance treatment pharmacogenetics

PubMed Central

Barratt, Daniel T; Coller, Janet K; Hallinan, Richard; Byrne, Andrew; White, Jason M; Foster, David JR; Somogyi, Andrew A

2012-01-01

Background: Genetic variability in ABCB1, encoding the P-glycoprotein efflux transporter, has been linked to altered methadone maintenance treatment dose requirements. However, subsequent studies have indicated that additional environmental or genetic factors may confound ABCB1 pharmacogenetics in different methadone maintenance treatment settings. There is evidence that genetic variability in OPRM1, encoding the mu opioid receptor, and ABCB1 may interact to affect morphine response in opposite ways. This study aimed to examine whether a similar gene-gene interaction occurs for methadone in methadone maintenance treatment. Methods: Opioid-dependent subjects (n = 119) maintained on methadone (15–300 mg/day) were genotyped for five single nucleotide polymorphisms of ABCB1 (61A > G; 1199G > A; 1236C > T; 2677G > T; 3435C > T), as well as for the OPRM1 118A > G single nucleotide polymorphism. Subjects’ methadone doses and trough plasma (R)-methadone concentrations (Ctrough) were compared between ABCB1 haplotypes (with and without controlling for OPRM1 genotype), and between OPRM1 genotypes (with and without controlling for ABCB1 haplotype). Results: Among wild-type OPRM1 subjects, an ABCB1 variant haplotype group (subjects with a wild-type and 61A:1199G:1236C:2677T:3435T haplotype combination, or homozygous for the 61A:1199G:1236C:2677T:3435T haplotype) had significantly lower doses (median ± standard deviation 35 ± 5 versus 180 ± 65 mg/day, P < 0.01) and Ctrough (78 ± 22 versus 177 ± 97 ng/mL, P < 0.05) than ABCB1 wild-type subjects. Among subjects with the most common ABCB1 haplotype combination (wild-type with 61A:1199G:1236T:2677T:3435T), the OPRM1 118 A/G genotype was associated with a significantly higher Ctrough than 118 A/A (250 ± 126 versus 108 ± 36 ng/mL, P = 0.016). No ABCB1 haplotype group or OPRM1 genotype was associated with dose or Ctrough without taking into account confounding genetic variability at the other locus. Therefore, two

[MODERN VIEWS ON THE PHARMACOGENETICS OF PAIN.

PubMed

Makharin, O A; Zhenilo, V M; Patyuchenko, O Yu

2017-09-01

Quality anesthesia during surgery and in the postoperative period remains a topical problem of modern anesthesiology. The study of genetic characteristics of a patient is a goal that may be allow us to develop a personalized approach to solve this problem. The purpose of the review is a synthesis of literature data about the influence of genetic factors on pain perception and its treatment. The review included information obtained from SCOPUS, MedLine, EMBASE. The search keywords were: pain, pharmacogenetics, polymorphism, analgesics.Describe the effect ofgene polymorphisms of OPRM, 5HTRIA, 5HTR2A, COMT GCHI, SCN9A, KCNSI, CACNA2D3, CACNG2, PTGSI, PTGS2, MDRJ/ABCB] on the perception of pain, and CYP2D6, CYP2C9, CYP3A4 on the pharmacokinetics and pharmacodynamics of medi- cations used in the treatment of pain.

Building Research Collaboration Networks--An Interpersonal Perspective for Research Capacity Building

ERIC Educational Resources Information Center

Huang, Jun Song

2014-01-01

While collaboration is increasingly recognized to be important for research, researchers' collaboration networks are still not adequately recognized as a form of research capacity in the literature. Research is a knowledge creation activity and interpersonal research collaboration networks are important for knowledge cross-fertilization and…

Evidence used in model-based economic evaluations for evaluating pharmacogenetic and pharmacogenomic tests: a systematic review protocol

PubMed Central

Peters, Jaime L; Cooper, Chris; Buchanan, James

2015-01-01

Introduction Decision models can be used to conduct economic evaluations of new pharmacogenetic and pharmacogenomic tests to ensure they offer value for money to healthcare systems. These models require a great deal of evidence, yet research suggests the evidence used is diverse and of uncertain quality. By conducting a systematic review, we aim to investigate the test-related evidence used to inform decision models developed for the economic evaluation of genetic tests. Methods and analysis We will search electronic databases including MEDLINE, EMBASE and NHS EEDs to identify model-based economic evaluations of pharmacogenetic and pharmacogenomic tests. The search will not be limited by language or date. Title and abstract screening will be conducted independently by 2 reviewers, with screening of full texts and data extraction conducted by 1 reviewer, and checked by another. Characteristics of the decision problem, the decision model and the test evidence used to inform the model will be extracted. Specifically, we will identify the reported evidence sources for the test-related evidence used, describe the study design and how the evidence was identified. A checklist developed specifically for decision analytic models will be used to critically appraise the models described in these studies. Variations in the test evidence used in the decision models will be explored across the included studies, and we will identify gaps in the evidence in terms of both quantity and quality. Dissemination The findings of this work will be disseminated via a peer-reviewed journal publication and at national and international conferences. PMID:26560056

Seventeen years of statin pharmacogenetics: a systematic review.

PubMed

Leusink, Maarten; Onland-Moret, N Charlotte; de Bakker, Paul I W; de Boer, Anthonius; Maitland-van der Zee, Anke H

2016-01-01

We evaluated the evidence of pharmacogenetic associations with statins in a systematic review. Two separate outcomes were considered of interest: modification of low-density lipoprotein cholesterol (LDL-C) response and modification of risk for cardiovascular events. In candidate gene studies, 141 loci were claimed to be associated with LDL-C response. Only 5% of these associations were positively replicated. In addition, six genome-wide association studies of LDL-C response identified common SNPs in APOE, LPA, SLCO1B1, SORT1 and ABCG2 at genome-wide significance. None of the investigated SNPs consistently affected the risk reduction for cardiovascular events. Only five genetic loci were consistently associated with LDL-C response. However, as effect sizes are modest, there is no evidence for the value of genetic testing in clinical practice.

Ethical reflections on pharmacogenetics and DNA banking in a cohort of HIV-infected patients

PubMed Central

de Montgolfier, Sandrine; Moutel, Grégoire; Duchange, Nathalie; Theodorou, Ioannis; Hervé, Christian; Leport, Catherine

2002-01-01

The aim of this study was to analyze ethical questions concerning the storage of human biological samples to be used in genetic analyses and pharmacogenetic research based on a French experience of DNA banking in a cohort of HIV-infected patients receiving protease inhibitor treatment (APROCO). We describe the ethical issues raised during the establishment of a DNA bank, including questions dealing with autonomy, benefit to the patient, information sharing and confidentiality as well as guarantees concerning the storage and use of DNA. We describe the practical applications of themes illustrated theoretically in the literature. Most of the points raised are not specific to HIV, but some of them may be more accurate due to the characteristics of the HIV population. The questions raised are not exhaustive and we conclude with specific points that remain to be defined. Our results are summarized in the memorandum and consent form presented in the appendices. This work should allow other researchers and members of evaluation committees to enrich their considerations and should stimulate discussion on this subject. PMID:12464796

Social Network Analysis of Biomedical Research Collaboration Networks in a CTSA Institution

PubMed Central

Bian, Jiang; Xie, Mengjun; Topaloglu, Umit; Hudson, Teresa; Eswaran, Hari; Hogan, William

2014-01-01

BACKGROUND The popularity of social networks has triggered a number of research efforts on network analyses of research collaborations in the Clinical and Translational Science Award (CTSA) community. Those studies mainly focus on the general understanding of collaboration networks by measuring common network metrics. More fundamental questions about collaborations still remain unanswered such as recognizing “influential” nodes and identifying potential new collaborations that are most rewarding. METHODS We analyzed biomedical research collaboration networks (RCNs) constructed from a dataset of research grants collected at a CTSA institution (i.e. University of Arkansas for Medical Sciences (UAMS)) in a comprehensive and systematic manner. First, our analysis covers the full spectrum of a RCN study: from network modeling to network characteristics measurement, from key nodes recognition to potential links (collaborations) suggestion. Second, our analysis employs non-conventional model and techniques including a weighted network model for representing collaboration strength, rank aggregation for detecting important nodes, and Random Walk with Restart (RWR) for suggesting new research collaborations. RESULTS By applying our models and techniques to RCNs at UAMS prior to and after the CTSA, we have gained valuable insights that not only reveal the temporal evolution of the network dynamics but also assess the effectiveness of the CTSA and its impact on a research institution. We find that collaboration networks at UAMS are not scale-free but small-world. Quantitative measures have been obtained to evident that the RCNs at UAMS are moving towards favoring multidisciplinary research. Moreover, our link prediction model creates the basis of collaboration recommendations with an impressive accuracy (AUC: 0.990, MAP@3: 1.48 and MAP@5: 1.522). Last but not least, an open-source visual analytical tool for RCNs is being developed and released through Github. CONCLUSIONS

Successful pharmacogenetics-based optimization of unboosted atazanavir plasma exposure in HIV-positive patients: a randomized, controlled, pilot study (the REYAGEN study).

PubMed

Bonora, S; Rusconi, S; Calcagno, A; Bracchi, M; Viganò, O; Cusato, J; Lanzafame, M; Trentalange, A; Marinaro, L; Siccardi, M; D'Avolio, A; Galli, M; Di Perri, G

2015-11-01

Atazanavir without ritonavir, despite efficacy and tolerability, shows low plasma concentrations that warrant optimization. In a randomized, controlled, pilot trial, stable HIV-positive patients on atazanavir/ritonavir (with tenofovir/emtricitabine) were switched to atazanavir. In the standard-dose arm, atazanavir was administered as 400 mg once daily, while according to patients' genetics (PXR, ABCB1 and SLCO1B1), in the pharmacogenetic arm: patients with unfavourable genotypes received 200 mg of atazanavir twice daily. EudraCT number: 2009-014216-35. Eighty patients were enrolled with balanced baseline characteristics. The average atazanavir exposure was 253 ng/mL (150-542) in the pharmacogenetic arm versus 111 ng/mL (64-190) in the standard-dose arm (P < 0.001); 28 patients in the pharmacogenetic arm (75.7%) had atazanavir exposure >150 ng/mL versus 14 patients (38.9%) in the standard-dose arm (P = 0.001). Immunovirological and laboratory parameters had a favourable outcome throughout the study with non-significant differences between study arms. Atazanavir plasma exposure is higher when the schedule is chosen according to the patient's genetic profile. © The Author 2015. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Key factors of clinical research network capacity building.

PubMed

Li, Guowei; Wu, Qianyu; Jin, Yanling; Vanniyasingam, Thuva; Thabane, Lehana

2018-01-01

In general, clinical research network capacity building refers to programs aimed at enhancing networks of researchers to conduct clinical research. Although in the literature there is a large body of research on how to develop and build capacity in clinical research networks, the conceptualizations and implementations remain controversial and challenging. Moreover, the experiences learnt from the past accomplishments and failures can assist in the future capacity building efforts to be more practical, effective and efficient. In this paper, we aim to provide an overview of capacity building in clinical research network by (1) identifying the key barriers to clinical research network capacity building, (2) providing insights into how to overcome those obstacles, and (3) sharing our experiences in collaborating with national and international partners to build capacity in clinical research networks. In conclusion, we have provided some insight into how to address the key factors of clinical research network capacity building and shared some empirical experiences. A successful capacity building practice requires a joint endeavor to procure sufficient resources and support from the relevant stakeholders, to ensure its efficiency, cost-effectiveness, and sustainability.

Research on NGN network control technology

NASA Astrophysics Data System (ADS)

Li, WenYao; Zhou, Fang; Wu, JianXue; Li, ZhiGuang

2004-04-01

Nowadays NGN (Next Generation Network) is the hotspot for discussion and research in IT section. The NGN core technology is the network control technology. The key goal of NGN is to realize the network convergence and evolution. Referring to overlay network model core on Softswitch technology, circuit switch network and IP network convergence realized. Referring to the optical transmission network core on ASTN/ASON, service layer (i.e. IP layer) and optical transmission convergence realized. Together with the distributing feature of NGN network control technology, on NGN platform, overview of combining Softswitch and ASTN/ASON control technology, the solution whether IP should be the NGN core carrier platform attracts general attention, and this is also a QoS problem on NGN end to end. This solution produces the significant practical meaning on equipment development, network deployment, network design and optimization, especially on realizing present network smooth evolving to the NGN. This is why this paper puts forward the research topic on the NGN network control technology. This paper introduces basics on NGN network control technology, then proposes NGN network control reference model, at the same time describes a realizable network structure of NGN. Based on above, from the view of function realization, NGN network control technology is discussed and its work mechanism is analyzed.

Exploring Practice-Research Networks for Critical Professional Learning

ERIC Educational Resources Information Center

Appleby, Yvon; Hillier, Yvonne

2012-01-01

This paper discusses the contribution that practice-research networks can make to support critical professional development in the Learning and Skills sector in England. By practice-research networks we mean groups or networks which maintain a connection between research and professional practice. These networks stem from the philosophy of…

Pharmacogenetic Risk Stratification in Angiotensin-Converting Enzyme Inhibitor-Treated Patients with Congestive Heart Failure: A Retrospective Cohort Study

PubMed Central

Nelveg-Kristensen, Karl Emil; Busk Madsen, Majbritt; Torp-Pedersen, Christian; Køber, Lars; Egfjord, Martin; Berg Rasmussen, Henrik; Riis Hansen, Peter

2015-01-01

Background Evidence for pharmacogenetic risk stratification of angiotensin-converting enzyme inhibitor (ACEI) treatment is limited. Therefore, in a cohort of ACEI-treated patients with congestive heart failure (CHF), we investigated the predictive value of two pharmacogenetic scores that previously were found to predict ACEI efficacy in patients with ischemic heart disease and hypertension, respectively. Score A combined single nucleotide polymorphisms (SNPs) of the angiotensin II receptor type 1 gene (rs275651 and rs5182) and the bradykinin receptor B1 gene (rs12050217). Score B combined SNPs of the angiotensin-converting enzyme gene (rs4343) and ABO blood group genes (rs495828 and rs8176746). Methods Danish patients with CHF enrolled in the previously reported Echocardiography and Heart Outcome Study were included. Subjects were genotyped and categorized according to pharmacogenetic scores A and B of ≤1, 2 and ≥3 each, and followed for up to 10 years. Difference in cumulative incidences of cardiovascular death and all-cause death were assessed by the cumulative incidence estimator. Survival was modeled by Cox proportional hazard analyses. Results We included 667 patients, of whom 80% were treated with ACEIs. Differences in cumulative incidences of cardiovascular death (P = 0.346 and P = 0.486) and all-cause death (P = 0.515 and P = 0.486) were not significant for score A and B, respectively. There was no difference in risk of cardiovascular death or all-cause death between subjects with score A ≤1 vs. 2 (HR 1.03 [95% CI 0.79–1.34] and HR 1.11 [95% CI 0.88–1.42]), score A ≤1 vs. ≥3 (HR 0.80 [95% CI 0.59–1.08] and HR 0.91 [95% CI 0.70–1.20]), score B ≤1 vs. 2 (HR 1.02 [95% CI 0.78–1.32] and HR 0.98 [95% CI 0.77–1.24]), and score B ≤1 vs. ≥3 (HR 1.03 [95% CI 0.75–1.41] and HR 1.05 [95% CI 0.79–1.40]), respectively. Conclusions We found no association between either of the analyzed pharmacogenetic scores and fatal outcomes in ACEI

Lymphatic Education & Research Network

MedlinePlus

Lymphatic Education & Research Network Donate Now Become a Supporting Member X Living with LYMPHEDEMA AND Lymphatic Disease FAQs About ... December 8, 2017 11.08.2017 The Lymphatic Education & Research Network… Read More > ASRM LE&RN Combined ...

Network Penetration Testing and Research

NASA Technical Reports Server (NTRS)

Murphy, Brandon F.

2013-01-01

This paper will focus the on research and testing done on penetrating a network for security purposes. This research will provide the IT security office new methods of attacks across and against a company's network as well as introduce them to new platforms and software that can be used to better assist with protecting against such attacks. Throughout this paper testing and research has been done on two different Linux based operating systems, for attacking and compromising a Windows based host computer. Backtrack 5 and BlackBuntu (Linux based penetration testing operating systems) are two different "attacker'' computers that will attempt to plant viruses and or NASA USRP - Internship Final Report exploits on a host Windows 7 operating system, as well as try to retrieve information from the host. On each Linux OS (Backtrack 5 and BlackBuntu) there is penetration testing software which provides the necessary tools to create exploits that can compromise a windows system as well as other operating systems. This paper will focus on two main methods of deploying exploits 1 onto a host computer in order to retrieve information from a compromised system. One method of deployment for an exploit that was tested is known as a "social engineering" exploit. This type of method requires interaction from unsuspecting user. With this user interaction, a deployed exploit may allow a malicious user to gain access to the unsuspecting user's computer as well as the network that such computer is connected to. Due to more advance security setting and antivirus protection and detection, this method is easily identified and defended against. The second method of exploit deployment is the method mainly focused upon within this paper. This method required extensive research on the best way to compromise a security enabled protected network. Once a network has been compromised, then any and all devices connected to such network has the potential to be compromised as well. With a compromised

A proposed international watershed research network

USGS Publications Warehouse

Osterkamp, W.R.; Gray, J.R.

2003-01-01

An “International Watershed Research Network” is to be an initial project of the Sino-U. S. Centers for Soil and Water Conservation and Environmental Protection. The Network will provide a fundamental database for research personnel of the Centers, as well as of the global research community, and is viewed as an important resource for their successful operation. Efforts are under way to (a) identify and select candidate watersheds, (b) develop standards and protocols for data collection and dissemination, and (c) specify other data sources on erosion, sediment transport, hydrology, and ancillary information of probable interest and use to participants of the Centers. The initial focus of the Network will be on water-deficient areas. Candidate watersheds for the Network are yet to be determined although likely selections include the Ansai Research Station, northern China, and the Walnut Gulch Experimental Watershed, Arizona, USA. The Network is to be patterned after the Vigil Network, an open-ended group of global sites and small drainage basins for which Internet-accessible geomorphic, hydrologic, and biological data are periodically collected or updated. Some types of data, using similar instruments and observation methods, will be collected at all watersheds selected for the Network. Other data from the watersheds that may reflect individual watershed characteristics and research objectives will be collected as well.

How does investment in research training affect the development of research networks and collaborations?

PubMed

Paina, Ligia; Ssengooba, Freddie; Waswa, Douglas; M'imunya, James M; Bennett, Sara

2013-05-20

Whether and how research training programs contribute to research network development is underexplored. The Fogarty International Center (FIC) has supported overseas research training programs for over two decades. FIC programs could provide an entry point in the development of research networks and collaborations. We examine whether FIC's investment in research training contributed to the development of networks and collaborations in two countries with longstanding FIC investments - Uganda and Kenya - and the factors which facilitated this process. As part of two case studies at Uganda's Makerere University and Kenya's University of Nairobi, we conducted 53 semi-structured in-depth interviews and nine focus group discussions. To expand on our case study findings, we conducted a focused bibliometric analysis on two purposively selected topic areas to examine scientific productivity and used online network illustration tools to examine the resulting network structures. FIC support made important contributions to network development. Respondents from both Uganda and Kenya confirmed that FIC programs consistently provided trainees with networking skills and exposure to research collaborations, primarily within the institutions implementing FIC programs. In both countries, networks struggled with inclusiveness, particularly in HIV/AIDS research. Ugandan respondents perceived their networks to be more cohesive than Kenyan respondents did. Network cohesiveness was positively correlated with the magnitude and longevity of FIC's programs. Support from FIC grants to local and regional research network development and networking opportunities, such as conferences, was rare. Synergies between FIC programs and research grants helped to solidify and maintain research collaborations. Networks developed where FIC's programs focused on a particular institution, there was a critical mass of trainees with similar interests, and investments for network development were available from

The child and adolescent psychiatry trials network (CAPTN): infrastructure development and lessons learned

PubMed Central

Shapiro, Mark; Silva, Susan G; Compton, Scott; Chrisman, Allan; DeVeaugh-Geiss, Joseph; Breland-Noble, Alfiee; Kondo, Douglas; Kirchner, Jerry; March, John S

2009-01-01

Background In 2003, the National Institute of Mental Health funded the Child and Adolescent Psychiatry Trials Network (CAPTN) under the Advanced Center for Services and Intervention Research (ACSIR) mechanism. At the time, CAPTN was believed to be both a highly innovative undertaking and a highly speculative one. One reviewer even suggested that CAPTN was "unlikely to succeed, but would be a valuable learning experience for the field." Objective To describe valuable lessons learned in building a clinical research network in pediatric psychiatry, including innovations intended to decrease barriers to research participation. Methods The CAPTN Team has completed construction of the CAPTN network infrastructure, conducted a large, multi-center psychometric study of a novel adverse event reporting tool, and initiated a large antidepressant safety registry and linked pharmacogenomic study focused on severe adverse events. Specific challenges overcome included establishing structures for network organization and governance; recruiting over 150 active CAPTN participants and 15 child psychiatry training programs; developing and implementing procedures for site contracts, regulatory compliance, indemnification and malpractice coverage, human subjects protection training and IRB approval; and constructing an innovative electronic casa report form (eCRF) running on a web-based electronic data capture system; and, finally, establishing procedures for audit trail oversight requirements put forward by, among others, the Food and Drug Administration (FDA). Conclusion Given stable funding for network construction and maintenance, our experience demonstrates that judicious use of web-based technologies for profiling investigators, investigator training, and capturing clinical trials data, when coupled to innovative approaches to network governance, data management and site management, can reduce the costs and burden and improve the feasibility of incorporating clinical research into

Patient-powered research networks aim to improve patient care and health research.

PubMed

Fleurence, Rachael L; Beal, Anne C; Sheridan, Susan E; Johnson, Lorraine B; Selby, Joe V

2014-07-01

The era of big data, loosely defined as the development and analysis of large or complex data sets, brings new opportunities to empower patients and their families to generate, collect, and use their health information for both clinical and research purposes. In 2013 the Patient-Centered Outcomes Research Institute launched a large national research network, PCORnet, that includes both clinical and patient-powered research networks. This article describes these networks, their potential uses, and the challenges they face. The networks are engaging patients, family members, and caregivers in four key ways: contributing data securely, with privacy protected; including diverse and representative groups of patients in research; prioritizing research questions, participating in research, and disseminating results; and participating in the leadership and governance of patient-powered research networks. If technical, regulatory, and organizational challenges can be overcome, PCORnet will allow research to be conducted more efficiently and cost-effectively and results to be disseminated quickly back to patients, clinicians, and delivery systems to improve patient health. Project HOPE—The People-to-People Health Foundation, Inc.

Asynchronous Video Streaming vs. Synchronous Videoconferencing for Teaching a Pharmacogenetic Pharmacotherapy Course

PubMed Central

2007-01-01

Objectives To compare students' performance and course evaluations for a pharmacogenetic pharmacotherapy course taught by synchronous videoconferencing method via the Internet and for the same course taught via asynchronous video streaming via the Internet. Methods In spring 2005, a pharmacogenetic therapy course was taught to 73 students located on Amarillo, Lubbock, and Dallas campuses using synchronous videoconferencing, and in spring 2006, to 78 students located on the same 3 campuses using asynchronous video streaming. A course evaluation was administered to each group at the end of the courses. Results Students in the asynchronous setting had final course grades of 89% ± 7% compared to the mean final course grade of 87% ± 7% in the synchronous group (p = 0.05). Regardless of which technology was used, average course grades did not differ significantly among the 3 campus sites. Significantly more of the students in the asynchronous setting agreed (57%) with the statement that they could read the lecture notes and absorb the content on their own without attending the class than students in the synchronous class (23%; chi-square test; p < 0.001). Conclusions Students in both asynchronous and synchronous settings performed well. However, students taught using asynchronous videotaped lectures had lower satisfaction with the method of content delivery, and preferred live interactive sessions or a mix of interactive sessions and asynchronous videos over delivery of content using the synchronous or asynchronous method alone. PMID:17429516

Bernard Lerer: Recipient of the 2014 Inaugural Werner Kalow Responsible Innovation Prize in Global Omics and Personalized Medicine (Pacific Rim Association for Clinical Pharmacogenetics)

PubMed Central

Aynacıoğlu, Şükrü; Bragazzi, Nicola Luigi; Dandara, Collet; Dove, Edward S.; Ferguson, Lynnette R.; Geraci, Christy Jo; Hafen, Ernst; Kesim, Belgin Eroğlu; Kolker, Eugene; Lee, Edmund J.D.; LLerena, Adrian; Nacak, Muradiye; Shimoda, Kazutaka; Someya, Toshiyuki; Srivastava, Sanjeeva; Tomlinson, Brian; Vayena, Effy; Warnich, Louise; Yaşar, Ümit

2014-01-01

Abstract This article announces the recipient of the 2014 inaugural Werner Kalow Responsible Innovation Prize in Global Omics and Personalized Medicine by the Pacific Rim Association for Clinical Pharmacogenetics (PRACP): Bernard Lerer, professor of psychiatry and director of the Biological Psychiatry Laboratory, Hadassah-Hebrew University Medical Center, Jerusalem, Israel. The Werner Kalow Responsible Innovation Prize is given to an exceptional interdisciplinary scholar who has made highly innovative and enduring contributions to global omics science and personalized medicine, with both vertical and horizontal (transdisciplinary) impacts. The prize is established in memory of a beloved colleague, mentor, and friend, the late Professor Werner Kalow, who cultivated the idea and practice of pharmacogenetics in modern therapeutics commencing in the 1950s. PRACP, the prize's sponsor, is one of the longest standing learned societies in the Asia-Pacific region, and was founded by Kalow and colleagues more than two decades ago in the then-emerging field of pharmacogenetics. In announcing this inaugural prize and its winner, we seek to highlight the works of prize winner, Professor Lerer. Additionally, we contextualize the significance of the prize by recalling the life and works of Professor Kalow and providing a brief socio-technical history of the rise of pharmacogenetics and personalized medicine as a veritable form of 21st century scientific practice. The article also fills a void in previous social science analyses of pharmacogenetics, by bringing to the fore the works of Kalow from 1995 to 2008, when he presciently noted the rise of yet another field of postgenomics inquiry—pharmacoepigenetics—that railed against genetic determinism and underscored the temporal and spatial plasticity of genetic components of drug response, with invention of the repeated drug administration (RDA) method that estimates the dynamic heritabilities of drug response. The prize goes a

Pharmacogenetic versus clinical dosing of warfarin in individuals of Chinese and African-American ancestry: assessment using data simulation.

PubMed

Syn, Nicholas L X; Lee, Soo-Chin; Brunham, Liam R; Goh, Boon-Cher

2015-10-01

Clinical trials of genotype-guided dosing of warfarin have yielded mixed results, which may in part reflect ethnic differences among study participants. However, no previous study has compared genotype-guided versus clinically guided or standard-of-care dosing in a Chinese population, whereas those involving African-Americans were underpowered to detect significant differences. We present a preclinical strategy that integrates pharmacogenetics (PG) and pharmacometrics to predict the outcome or guide the design of dosing strategies for drugs that show large interindividual variability. We use the example of warfarin and focus on two underrepresented groups in warfarin research. We identified the parameters required to simulate a patient population and the outcome of dosing strategies. PG and pharmacogenetic plus loading (PG+L) algorithms that take into account a patient's VKORC1 and CYP2C9 genotype status were considered and compared against a clinical (CA) algorithm for a simulated Chinese population using a predictive Monte Carlo and pharmacokinetic-pharmacodynamic framework. We also examined a simulated population of African-American ancestry to assess the robustness of the model in relation to real-world clinical trial data. The simulations replicated similar trends observed with clinical data in African-Americans. They further predict that the PG+L regimen is superior to both the CA and the PG regimen in maximizing percentage time in therapeutic range in a Chinese cohort, whereas the CA regimen poses the highest risk of overanticoagulation during warfarin initiation. The findings supplement the literature with an unbiased comparison of warfarin dosing algorithms and highlights interethnic differences in anticoagulation control.

Research in Network Management Techniques for Tactical Data Communications Network.

DTIC Science & Technology

1982-09-01

the control period. Research areas include Packet Network modelling, adaptive network routing, network design algorithms, network design techniques...contro!lers are designed to perform their limited tasks optimally. For the dynamic routing problem considered here, the local controllers are node...feedback to finding in optimum stead-o-state routing (static strategies) under non - control which can be easily implemented in real time. congested

Regional Research Networking: A Stimulus to Research Collaboration and Research Productivity.

ERIC Educational Resources Information Center

McElmurry, Beverly J.; Minckley, Barbara B.

1986-01-01

Models for collegial networking as a means of increasing the participants' scholarly productivity are presented. A Midwestern historical methodology research interest group is described as an example of the long-term benefits of forming networks of scholars. (MSE)

The physical therapy clinical research network (PTClinResNet): methods, efficacy, and benefits of a rehabilitation research network.

PubMed

Winstein, Carolee; Pate, Patricia; Ge, Tingting; Ervin, Carolyn; Baurley, James; Sullivan, Katherine J; Underwood, Samantha J; Fowler, Eileen G; Mulroy, Sara; Brown, David A; Kulig, Kornelia; Gordon, James; Azen, Stanley P

2008-11-01

This article describes the vision, methods, and implementation strategies used in building the infrastructure for PTClinResNet, a clinical research network designed to assess outcomes for health-related mobility associated with evidence-based physical therapy interventions across and within four different disability groups. Specific aims were to (1) create the infrastructure necessary to develop and sustain clinical trials research in rehabilitation, (2) generate evidence to evaluate the efficacy of resistance exercise-based physical interventions designed to improve muscle performance and movement skills, and (3) provide education and training opportunities for present and future clinician-researchers and for the rehabilitation community at-large in its support of evidence-based practice. We present the network's infrastructure, development, and several examples that highlight the benefits of a clinical research network. We suggest that the network structure is ideal for building research capacity and fostering multisite, multiinvestigator clinical research projects designed to generate evidence for the efficacy of rehabilitation interventions.

Pharmacogenetics: progress, pitfalls and clinical potential for coronary heart disease.

PubMed

Humphries, Steve E; Hingorani, Aroon

2006-02-01

Much has been written about the potential of pharmacogenetic testing to inform therapy based on an individual's genetic makeup, and to decide the most effective choice of available drugs, or to avoid dangerous side effects. Currently, there is little hard data for either in the field of cardiovascular disease. The usual approach has been opportunistic use of drug trials in unrelated patients, and to look for differences in response or outcome by "candidate gene" genotype, for example genes coding for drug metabolising enzymes (activators and metabolisers), and enzymes and receptors involved in lipid metabolism, adrenergic response, etc. As with all association studies, initially promising results have often failed the test of replication in larger studies, and the relationship between the CETP Taq-I variant and response to statins has now been disproved. The strongest data to date is the report [Chasman, D.I., Posada, D., Subrahmanyan, L., Cook, N.R., Stanton Jr., V.P., Ridker, P.M., 2004. Pharmacogenetic study of statin therapy and cholesterol reduction. J. Am. Med. Assoc. 291, 2821-2827] of a poorer cholesterol-lowering response to Pravastatin in the 7% of patients carrying a certain haplotype of the HMG CoA reductase gene (14% fall versus 19%), but if this is overcome simply by a higher dose, it is of little clinical relevance. Currently, the best example of avoiding side effects is determining genotype at the CYP2C9 locus with respect of warfarin treatment, since carriers for functional variants (>20% of the population) require lower doses for optimal anticoagulation, and homozygotes, although rare, may well experience serious bleeding if given a usual dose. The full potential of this field will only be realised with much further work.

Research Networks, Mentorship and Sustainability Knowledge

NASA Astrophysics Data System (ADS)

Kafle, A.; Mukhopadhyay, P.; Nepal, M.; Shyamsundar, P.

2015-12-01

In South Asia, a majority of institutions are ill-equipped to undertake research on multi-disciplinary environmental problems, though these problems are increasing at a fast rate and connected to the region's poverty and growth objectives. In this context, the South Asian Network for Development and Environmental Economics (SANDEE) tries to fill a research, training and knowledge gap by building skills in the area of Environment and Development Economics. In this paper, the authors argue that research networks contribute to the growth of sustainability knowledge through (a) knowledge creation, (b) knowledge transfer and (c) knowledge deepening. The paper tries to show the relationship between capacity building, mentorship and research scholarship. It demonstrates that researchers, by associating with the network and its multiple training and mentoring processes, are able to build skills, change curricula and deliver useful knowledge products. The paper discusses the need for interdisciplinary research and the challenges of bridging the gap between research outputs and policy reforms.

[Pharmacogenetics in anesthesia and intensive care medicine : Clinical and legal challenges exemplified by malignant hyperthermia].

PubMed

Klingler, W; Pfenninger, E

2016-05-01

Pharmacotherapy is a key component of anesthesiology and intensive care medicine. The individual genetic profile influences not only the effect of pharmaceuticals but can also completely alter the mode of action. New technologies for genetic screening (e.g. next generation sequencing) and increasing knowledge of molecular pathways foster the disclosure of pharmacogenetic syndromes, which are classified as rare diseases. Taking into account the high genetic variability in humans and over 8000 known rare diseases, up to 20 % of the population may be affected. In summary, rare diseases are not rare. Most pharmacogenetic syndromes lead to a weakening or loss of pharmacological action. In contrast, malignant hyperthermia (MH), which is the most relevant pharmacogenetic syndrome for anesthesia, is characterized by a pharmacologically induced overactivation of calcium metabolism in skeletal muscle. Volatile anesthetic agents and succinylcholine trigger life-threatening hypermetabolic crises. Emergency treatment is based on inhibition of the calcium release channel of the sarcoplasmic reticulum by dantrolene. After an adverse pharmacological event patients must be informed and a clarification consultation must be carried out during which the hereditory character of MH is explained. The patient should be referred to a specialist MH center where a predisposition can be diagnosed by the functional in vitro contracture test from a muscle biopsy. Additional molecular genetic investigations can yield mutations in the genes for calcium-regulating proteins in skeletal muscle, e.g. ryanodine receptor 1 (RyR1) and calcium voltage-gated channel subunit alpha 1S (CACNA1S). Currently, an association to MH has only been shown for 35 mutations out of more than 400 known and probably hundreds of unknown genetic variations. Furthermore, MH predisposition is not excluded by negative mutation screening. For anesthesiological patient safety it is crucial to identify individuals at risk and

Creatiing a Collaborative Research Network for Scientists

NASA Astrophysics Data System (ADS)

Gunn, W.

2012-12-01

This abstract proposes a discussion of how professional science communication and scientific cooperation can become more efficient through the use of modern social network technology, using the example of Mendeley. Mendeley is a research workflow and collaboration tool which crowdsources real-time research trend information and semantic annotations of research papers in a central data store, thereby creating a "social research network" that is emergent from the research data added to the platform. We describe how Mendeley's model can overcome barriers for collaboration by turning research papers into social objects, making academic data publicly available via an open API, and promoting more efficient collaboration. Central to the success of Mendeley has been the creation of a tool that works for the researcher without the requirement of being part of an explicit social network. Mendeley automatically extracts metadata from research papers, and allows a researcher to annotate, tag and organize their research collection. The tool integrates with the paper writing workflow and provides advanced collaboration options, thus significantly improving researchers' productivity. By anonymously aggregating usage data, Mendeley enables the emergence of social metrics and real-time usage stats on top of the articles' abstract metadata. In this way a social network of collaborators, and people genuinely interested in content, emerges. By building this research network around the article as the social object, a social layer of direct relevance to academia emerges. As science, particularly Earth sciences with their large shared resources, become more and more global, the management and coordination of research is more and more dependent on technology to support these distributed collaborations.

Racial differences in advanced colorectal cancer outcomes and pharmacogenetics: a subgroup analysis of a large randomized clinical trial.

PubMed

Sanoff, Hanna K; Sargent, Daniel J; Green, Erin M; McLeod, Howard L; Goldberg, Richard M

2009-09-01

Racial disparities in colorectal cancer (CRC) survival are documented, but there are few data on comparative response to chemotherapy. A subgroup analysis of a multisite National Cancer Institute-sponsored trial (N9741) was performed comparing outcomes of black and white patients with metastatic CRC receiving uniform treatment. Adverse events (AEs), response rate (RR), time to progression (TTP), overall survival (OS), and dose-intensity were examined as a function of self-reported race in 1,412 patients treated with irinotecan/fluorouracil, fluorouracil/oxaliplatin, or irinotecan/oxaliplatin. Pharmacogenetic analysis was performed on 486 patients with blood available for germline DNA analysis. OS was 1.5 months shorter and TTP was 0.6 months shorter in black than white patients (OS: hazard ratio [HR] = 1.13; 95% CI, 0.90 to 1.42; TTP: HR = 0.91, 95% CI, 0.73 to 1.13); neither difference was statistically significant. RR was significantly higher in whites (41%) than blacks (28%; P = .008). Grade 3 or greater AEs were also higher in whites (48%) than blacks (34%; P = .004). These relationships were maintained in multivariate models adjusting for arm, age, sex, and performance status. There was no difference in dose-intensity of delivered therapy. Significant racial differences in prevalence of pharmacogenetic variants were observed, although small sample size precluded investigating the relationship between treatment, race, and genotype. OS and TTP are similar in black and white patients treated per protocol with standardized therapy for metastatic CRC. However, RR and AEs vary considerably by race. The marked racial differences in relevant pharmacogenetics, a potential explanation for differing RR and AEs, are worthy of future study.

Optogenetics and pharmacogenetics: principles and applications.

PubMed

Jiang, Jingwei; Cui, Huxing; Rahmouni, Kamal

2017-12-01

Remote and selective spatiotemporal control of the activity of neurons to regulate behavior and physiological functions has been a long-sought goal in system neuroscience. Identification and subsequent bioengineering of light-sensitive ion channels (e.g., channelrhodopsins, halorhodopsin, and archaerhodopsins) from the bacteria have made it possible to use light to artificially modulate neuronal activity, namely optogenetics. Recent advance in genetics has also allowed development of novel pharmacological tools to selectively and remotely control neuronal activity using engineered G protein-coupled receptors, which can be activated by otherwise inert drug-like small molecules such as the designer receptors exclusively activated by designer drug, a form of chemogenetics. The cutting-edge optogenetics and pharmacogenetics are powerful tools in neuroscience that allow selective and bidirectional modulation of the activity of defined populations of neurons with unprecedented specificity. These novel toolboxes are enabling significant advances in deciphering how the nervous system works and its influence on various physiological processes in health and disease. Here, we discuss the fundamental elements of optogenetics and chemogenetics approaches and some of the applications that yielded significant advances in various areas of neuroscience and beyond. Copyright © 2017 the American Physiological Society.

Pharmacodynamic, pharmacokinetic and pharmacogenetic aspects of drugs used in the treatment of Alzheimer's disease.

PubMed

Noetzli, Muriel; Eap, Chin B

2013-04-01

With the aging population and its rapidly increasing prevalence, dementia has become an important public health concern in developed and developing countries. To date, the pharmacological treatment is symptomatic and based on the observed neurotransmitter disturbances. The four most commonly used drugs are donepezil, galantamine, rivastigmine and memantine. Donepezil, galantamine and rivastigmine are acetylcholinesterase inhibitors with different pharmacodynamic and pharmacokinetic profiles. Donepezil inhibits selectively the acetylcholinesterase and has a long elimination half-life (t(1/2)) of 70 h. Galantamine is also a selective acetylcholinesterase inhibitor, but also modulates presynaptic nicotinic receptors. It has a t(1/2) of 6-8 h. Donepezil and galantamine are mainly metabolised by cytochrome P450 (CYP) 2D6 and CYP3A4 in the liver. Rivastigmine is a so-called 'pseudo-irreversible' inhibitor of acetylcholinesterase and butyrylcholinesterase. The t(1/2) of the drug is very short (1-2 h), but the duration of action is longer as the enzymes are blocked for around 8.5 and 3.5 h, respectively. Rivastigmine is metabolised by esterases in liver and intestine. Memantine is a non-competitive low-affinity antagonist of the NMDA receptor with a t(1/2) of 70 h. Its major route of elimination is unchanged via the kidneys. Addressing the issue of inter-patient variability in treatment response might be of special importance for the vulnerable population taking anti-dementia drugs. Pharmacogenetic considerations might help to avoid multiple medication changes due to non-response and/or adverse events. Some pharmacogenetic studies conducted on donepezil and galantamine reported an influence of the CYP2D6 genotype on the pharmacokinetics of the drugs and/or on the response to treatment. Moreover, polymorphisms in genes of the cholinergic markers acetylcholinesterase, butyrylcholinesterase, choline acetyltransferase and paraoxonase were found to be associated with better

Innovative research of AD HOC network mobility model

NASA Astrophysics Data System (ADS)

Chen, Xin

2017-08-01

It is difficult for researchers of AD HOC network to conduct actual deployment during experimental stage as the network topology is changeable and location of nodes is unfixed. Thus simulation still remains the main research method of the network. Mobility model is an important component of AD HOC network simulation. It is used to describe the movement pattern of nodes in AD HOC network (including location and velocity, etc.) and decides the movement trail of nodes, playing as the abstraction of the movement modes of nodes. Therefore, mobility model which simulates node movement is an important foundation for simulation research. In AD HOC network research, mobility model shall reflect the movement law of nodes as truly as possible. In this paper, node generally refers to the wireless equipment people carry. The main research contents include how nodes avoid obstacles during movement process and the impacts of obstacles on the mutual relation among nodes, based on which a Node Self Avoiding Obstacle, i.e. NASO model is established in AD HOC network.

Collaborative networks for both improvement and research.

PubMed

Clancy, Carolyn M; Margolis, Peter A; Miller, Marlene

2013-06-01

Moving significant therapeutic discoveries beyond early biomedical translation or T1 science and into practice involves: (1) T2 science, identifying "the right treatment for the right patient in the right way at the right time" (eg, patient-centered outcomes research) and tools to implement this knowledge (eg, guidelines, registries); and (2) T3 studies addressing how to achieve health care delivery change. Collaborative improvement networks can serve as large-scale, health system laboratories to engage clinicians, researchers, patients, and parents in testing approaches to translate research into practice. Improvement networks are of particular importance for pediatric T2 and T3 research, as evidence to establish safety and efficacy of therapeutic interventions in children is often lacking. Networks for improvement and research are also consistent with the Institute of Medicine's Learning Healthcare Systems model in which learning networks provide a system for improving care and outcomes and generate new knowledge in near real-time. Creation of total population registries in collaborative network sites provides large, representative study samples with high-quality data that can be used to generate evidence and to inform clinical decision-making. Networks use collaboration, data, and quality-improvement methods to standardize practice. Therefore, variation in outcomes due to unreliable and unnecessary care delivery is reduced, increasing statistical power, and allowing a consistent baseline from which to test new strategies. In addition, collaborative networks for improvement and research offer the opportunity to not only make improvements but also to study improvements to determine which interventions and combination of strategies work best in what settings.

A research on the application of software defined networking in satellite network architecture

NASA Astrophysics Data System (ADS)

Song, Huan; Chen, Jinqiang; Cao, Suzhi; Cui, Dandan; Li, Tong; Su, Yuxing

2017-10-01

Software defined network is a new type of network architecture, which decouples control plane and data plane of traditional network, has the feature of flexible configurations and is a direction of the next generation terrestrial Internet development. Satellite network is an important part of the space-ground integrated information network, while the traditional satellite network has the disadvantages of difficult network topology maintenance and slow configuration. The application of SDN technology in satellite network can solve these problems that traditional satellite network faces. At present, the research on the application of SDN technology in satellite network is still in the stage of preliminary study. In this paper, we start with introducing the SDN technology and satellite network architecture. Then we mainly introduce software defined satellite network architecture, as well as the comparison of different software defined satellite network architecture and satellite network virtualization. Finally, the present research status and development trend of SDN technology in satellite network are analyzed.

Connecting the Dots: Understanding the Flow of Research Knowledge within a Research Brokering Network

ERIC Educational Resources Information Center

Rodway, Joelle

2015-01-01

Networks are frequently cited as an important knowledge mobilization strategy; however, there is little empirical research that considers how they connect research and practice. Taking a social network perspective, I explore how central office personnel find, understand and share research knowledge within a research brokering network. This mixed…

Thiopurine S-Methyltransferase as a Pharmacogenetic Biomarker: Significance of Testing and Review of Major Methods

PubMed Central

Asadov, Chingiz; Aliyeva, Gunay; Mustafayeva, Kamala

2017-01-01

Background: Thiopurine S-methyltransferase (TPMT) enzyme metabolizes thiopurine drugs which are widely used in various disciplines as well as in leukemias. Individual enzyme activity varies depending on the genetic polymorphisms of TPMT gene located at chromosome 6. Up to 14% of popu-lation is known to have a decreased enzyme activity, and if treated with standard doses of thiopurines, these individuals are at a high risk of severe Adverse Drug Reactions (ADR) as myelosuppression, gas-trointestinal intolerance, pancreatitis and hypersensitivity. However, TPMT-deficient patients can suc-cessfully be treated with decreased thiopurine doses if enzyme status is identified by a prior testing. TPMT status identification is a pioneering experience in application of pharmacogenetic testing in clini-cal settings. 4 TPMT (*2, *3A, *3B, *3C) alleles are known to account for 80-95% of a decreased en-zyme activity, and therefore, identifying the presence of these alleles supported by phenotypic measure-ment of the enzyme activity can reveal patient’s TPMT status. Evaluation of the levels of thiopurine me-tabolites further supports the practice of appropriate dose adjustment by providing the efficient monitor-ing of drug cytotoxicity. Conclusion: We hereby review the thiopurine pharmacogenetics and the methods applied in common practice to evaluate patient’s TPMT status. PMID:28552060

Molecular actions and clinical pharmacogenetics of lithium therapy

PubMed Central

Can, Adem; Schulze, Thomas G.; Gould, Todd D.

2014-01-01

Mood disorders, including bipolar disorder and depression, are relatively common human diseases for which pharmacological treatment options are often not optimal. Among existing pharmacological agents and mood stabilizers used for the treatment of mood disorders, lithium has a unique clinical profile. Lithium has efficacy in the treatment of bipolar disorder generally, and in particular mania, while also being useful in the adjunct treatment of refractory depression. In addition to antimanic and adjunct antidepressant efficacy, lithium is also proven effective in the reduction of suicide and suicidal behaviors. However, only a subset of patients manifests beneficial responses to lithium therapy and the underlying genetic factors of response are not exactly known. Here we discuss preclinical research suggesting mechanisms likely to underlie lithium’s therapeutic actions including direct targets inositol monophosphatase and glycogen synthase kinase-3 (GSK-3) among others, as well as indirect actions including modulation of neurotrophic and neurotransmitter systems and circadian function. We follow with a discussion of current knowledge related to the pharmacogenetic underpinnings of effective lithium therapy in patients within this context. Progress in elucidation of genetic factors that may be involved in human response to lithium pharmacology has been slow, and there is still limited conclusive evidence for the role of a particular genetic factor. However, the development of new approaches such as genome-wide association studies (GWAS), and increased use of genetic testing and improved identification of mood disorder patients sub-groups will lead to improved elucidation of relevant genetic factors in the future. PMID:24534415

The Nordic Health Promotion Research Network (NHPRN).

PubMed

Ringsberg, Karin C

2015-08-01

The Nordic Health Promotion Research Network (NHPRN) was established in 2007 at the Nordic School of Public Health (NHV). This article aims to describe the foundation of the NHPRN, the development and the present status of the work of NHPRN. The NHPRN consists of about 50 senior and junior researchers from all Nordic countries. It is a working network that aims to develop the theoretical understanding of health promotion, to create research cooperation in health promotion from a Nordic perspective and to extend the scope of health promotion through education. Network members meet biannually to discuss and further develop research within the field and are also responsible for the Nordic conference on Health Promotion, organized every 3 years. The NHV hosted the network between 2007 and 2014; and the World Health Organisation (WHO) will assume this role in 2015. © 2015 the Nordic Societies of Public Health.

Pharmacogenetics and pharmacogenomics: a bridge to individualized cancer therapy

PubMed Central

Weng, Liming; Zhang, Li; Peng, Yan; Huang, R Stephanie

2013-01-01

In the past decade, advances in pharmacogenetics and pharmacogenomics (PGx) have gradually unveiled the genetic basis of interindividual differences in drug responses. A large portion of these advances have been made in the field of anticancer therapy. Currently, the US FDA has updated the package inserts of approximately 30 anticancer agents to include PGx information. Given the complexity of this genetic information (e.g., tumor mutation and gene overexpression, chromosomal translocation and germline variations), as well as the variable level of scientific evidence, the FDA recommendation and potential action needed varies among drugs. In this review, we have highlighted some of these PGx discoveries for their scientific values and utility in improving therapeutic efficacy and reducing side effects. Furthermore, examples are also provided for the role of PGx in new anticancer drug development by revealing novel druggable targets. PMID:23394393

Clinical outcomes and genome-wide association for a brain methylation site in an antidepressant pharmacogenetics study in Mexican Americans.

PubMed

Wong, Ma-Li; Dong, Chuanhui; Flores, Deborah L; Ehrhart-Bornstein, Monika; Bornstein, Stefan; Arcos-Burgos, Mauricio; Licinio, Julio

2014-12-01

The authors compared the effectiveness of fluoxetine and desipramine treatment in a prospective double-blind pharmacogenetics study in first-generation Mexican Americans and examined the role of whole-exome functional gene variations in the patients' antidepressant response. A total of 232 Mexican Americans who met DSM-IV criteria for major depressive disorder were randomly assigned to receive 8 weeks of double-blind treatment with desipramine (50-200 mg/day) or fluoxetine (10-40 mg/day) after a 1-week placebo lead-in period. Outcome measures included the Hamilton Depression Rating Scale (HAM-D), the Hamilton Anxiety Rating Scale, and the Beck Depression Inventory. At week 8, whole-exome genotyping data were obtained for 36 participants who remitted and 29 who did not respond to treatment. Compared with desipramine treatment, fluoxetine treatment was associated with a greater reduction in HAM-D score, higher response and remission rates, shorter time to response and remission, and lower incidences of anticholinergic and cardiovascular side effects. Pharmacogenetics analysis showed that exm-rs1321744 achieved exome-wide significance for treatment remission. This variant is located in a brain methylated DNA immunoprecipitation sequencing site, which suggests that it may be involved in epigenetic regulation of neuronal gene expression. This and two other common gene variants provided a highly accurate cross-validated predictive model for treatment remission of major depression (receiver operating characteristic integral=0.95). Compared with desipramine, fluoxetine treatment showed a more rapid reduction of HAM-D score and a lower incidence of side effects in a population comprising primarily first-generation Mexican Americans with major depression. This study's pharmacogenetics approach strongly implicates the role of functional variants in antidepressant treatment response.

No longer simply a Practice-based Research Network (PBRN) health improvement networks.

PubMed

Williams, Robert L; Rhyne, Robert L

2011-01-01

While primary care Practice-based Research Networks are best known for their original, research purpose, evidence accumulating over the last several years is demonstrating broader values of these collaborations. Studies have demonstrated their role in quality improvement and practice change, in continuing professional education, in clinician retention in medically underserved areas, and in facilitating transition of primary care organization. A role in informing and facilitating health policy development is also suggested. Taking into account this more robust potential, we propose a new title, the Health Improvement Network, and a new vision for Practice-based Research Networks.

Community pharmacist participation in a practice-based research network: a report from the Medication Safety Research Network of Indiana (Rx-SafeNet).

PubMed

Patel, Puja; Hemmeger, Heather; Kozak, Mary Ann; Gernant, Stephanie A; Snyder, Margie E

2015-01-01

To describe the experiences and opinions of pharmacists serving as site coordinators for the Medication Safety Research Network of Indiana (Rx-SafeNet). Retail chain, independent, and hospital/health system outpatient community pharmacies throughout Indiana, with a total of 127 pharmacy members represented by 26 site coordinators. Rx-SafeNet, a statewide practice-based research network (PBRN) formed in 2010 and administered by the Purdue University College of Pharmacy. Barriers and facilitators to participation in available research studies, confidence participating in research, and satisfaction with overall network communication. 22 of 26 site coordinators participated, resulting in an 85% response rate. Most (72.2%) of the respondents had received a doctor of pharmacy degree, and 13.6% had postgraduate year (PGY)1 residency training. The highest reported benefits of PBRN membership were an enhanced relationship with the Purdue University College of Pharmacy (81% agreed or strongly agreed) and enhanced professional development (80% agreed or strongly agreed). Time constraints were identified as the greatest potential barrier to network participation, reported by 62% of respondents. In addition, the majority (59%) of survey respondents identified no prior research experience. Last, respondents' confidence in performing research appeared to increase substantially after becoming network members, with 43% reporting a lack of confidence in engaging in research before joining the network compared with 90% reporting confidence after joining the network. In general, Rx-SafeNet site coordinators appeared to experience increased confidence in research engagement after joining the network. While respondents identified a number of benefits associated with network participation, concerns about potential time constraints remained a key barrier to participation. These findings will assist network leadership in identifying opportunities to positively increase member participation

Scottish Stroke Research Network: the first three years.

PubMed

McCormick, K; Langhorne, P; Graham, F E J; McFarlane, C

2010-08-01

Research networks were introduced in the UK to facilitate and improve clinical research and stroke was seen as a priority topic for local research network development. The Scottish Stroke Research Network (SSRN) is one of 11 stroke research networks in the UK. In this article we review the progress of the Scottish Stroke Research Network in the three years since inception. Between 2006-2009 the number of active hospital research sites has increased from 10 to 22 expanding to involve 20 stroke research nurses. There was a corresponding 58% increase in recruitment of participants into stroke studies, from 376 in 2006/07 to 594 in 2008/09. The majority (17/20) of our current studies are interventional. Data from one of these, the CLOTs trial (Clots in Legs Or sTocking after Stroke), demonstrates that the annual recruitment in Scotland increased from a median of 94 (range 6-122) patients per year in the six years before the SSRN, to 140 (135-158) patients per year after SSRN involvement. We currently screen about 50% of Scottish stroke patients and approximately 5% of Scottish stroke patients are participating in research studies that we support. The SSRN has made good progress in the first three years. Increasing the recruitment of screened patients remains a challenge.

Stories in Networks and Networks in Stories: A Tri-Modal Model for Mixed-Methods Social Network Research on Teachers

ERIC Educational Resources Information Center

Baker-Doyle, Kira J.

2015-01-01

Social network research on teachers and schools has risen exponentially in recent years as an innovative method to reveal the role of social networks in education. However, scholars are still exploring ways to incorporate traditional quantitative methods of Social Network Analysis (SNA) with qualitative approaches to social network research. This…

Optimizing trial design in pharmacogenetics research: comparing a fixed parallel group, group sequential, and adaptive selection design on sample size requirements.

PubMed

Boessen, Ruud; van der Baan, Frederieke; Groenwold, Rolf; Egberts, Antoine; Klungel, Olaf; Grobbee, Diederick; Knol, Mirjam; Roes, Kit

2013-01-01

Two-stage clinical trial designs may be efficient in pharmacogenetics research when there is some but inconclusive evidence of effect modification by a genomic marker. Two-stage designs allow to stop early for efficacy or futility and can offer the additional opportunity to enrich the study population to a specific patient subgroup after an interim analysis. This study compared sample size requirements for fixed parallel group, group sequential, and adaptive selection designs with equal overall power and control of the family-wise type I error rate. The designs were evaluated across scenarios that defined the effect sizes in the marker positive and marker negative subgroups and the prevalence of marker positive patients in the overall study population. Effect sizes were chosen to reflect realistic planning scenarios, where at least some effect is present in the marker negative subgroup. In addition, scenarios were considered in which the assumed 'true' subgroup effects (i.e., the postulated effects) differed from those hypothesized at the planning stage. As expected, both two-stage designs generally required fewer patients than a fixed parallel group design, and the advantage increased as the difference between subgroups increased. The adaptive selection design added little further reduction in sample size, as compared with the group sequential design, when the postulated effect sizes were equal to those hypothesized at the planning stage. However, when the postulated effects deviated strongly in favor of enrichment, the comparative advantage of the adaptive selection design increased, which precisely reflects the adaptive nature of the design. Copyright © 2013 John Wiley & Sons, Ltd.

Research Networks Map | Division of Cancer Prevention

Cancer.gov

The Division of Cancer Prevention supports major scientific collaborations and research networks at more than 100 sites across the United States. Seven Major Programs' sites are shown on this map. | The Division of Cancer Prevention supports major scientific collaborations and research networks at more than 100 sites across the United States.

Reaching Out: IDRC-HDFS Research Network (India). Final Report.

ERIC Educational Resources Information Center

Saraswathi, T. S.; And Others

This report documents the activities of the Research Network, a coordinated effort of the International Development Research Center (IDRC) and the Human Development and Family Studies (HDFS) Department of Baroda University (India) during the period January 1990 to June 1993. The Research Network aimed to establish a network of consultative…

Evolution of the research collaboration network in a productive department.

PubMed

Katerndahl, David

2012-02-01

Understanding collaboration networks can facilitate the research growth of new or developing departments. The purpose of this study was to use social network analysis to understand how the research collaboration network evolved within a productive department. Over a 13-year period, a departmental faculty completed an annual survey describing their research collaborations. Data were analyzed using social network analysis. Network measures focused on connectedness, distance, groupings and heterogeneity of distribution, while measures for the research director and external collaboration focused on centrality and roles within the network. Longitudinal patterns of network collaboration were assessed using Simulation Investigation for Empirical Network Analysis software (University of Groningen, Groningen, Netherlands). Based upon the number of active research projects, research development can be divided into three phases. The initial development phase was characterized by increasing centralization and collaboration focused within a single subject area. During the maintenance phase, measures went through cycles, possibly because of changes in faculty composition. While the research director was not a 'key player' within the network during the first several years, external collaboration played a central role during all phases. Longitudinal analysis found that forming ties was more likely when the opportunity for network closure existed and when those around you are principal investigators (PIs). Initial development of research relied heavily upon a centralized network involving external collaboration; a central position of the research director during research development was not important. Changes in collaboration depended upon faculty gender and tenure track as well as transitivity and the 'popularity of PIs'. © 2011 Blackwell Publishing Ltd.

NIHR Clinical Research Networks: what they do and how they help paediatric research.

PubMed

Lythgoe, Hanna; Price, Victoria; Poustie, Vanessa; Attar, Sabah; Hawcutt, Daniel; Preston, Jennifer; Beresford, Michael W

2017-08-01

This review provides paediatricians with an update on the new structure of the National Institute for Health Research's (NIHR) Clinical Research Network (CRN): Children and its role within the wider NIHR infrastructure. The network supports delivery of high-quality research within the NHS in England and supports researchers, through provision of staff and resources, with feasibility, site set-up, patient recruitment and study management. Since 2013, over 80% of commercial contract studies running within the UK sat within the UKCRN Portfolio. Of the diverse, increasing portfolio of studies supported by the network, many studies are interventional, with 33% being randomised controlled studies. Recruitment to studies supported by the network through the Children's Portfolio has consistently improved. Over 200 000 participants have been recruited to the Children's Portfolio studies to date, and there are currently approximately 500 studies open to recruitment. The CRN: Children has successfully involved patients and the public in all aspects of study design and delivery, including through the work of Generation R. Challenges remain in conducting paediatric research and the network is committed to supporting Children's research and further building on its achievements to date. Education and engagement of paediatricians within the network and research is important to further improving quality and delivery of paediatric research. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

Praxis-based research networks: An emerging paradigm for research that is rigorous, relevant, and inclusive.

PubMed

Werner, James J; Stange, Kurt C

2014-01-01

Practice-based research networks (PBRNs) have developed a grounded approach to conducting practice-relevant and translational research in community practice settings. Seismic shifts in the health care landscape are shaping PBRNs that work across organizational and institutional margins to address complex problems. Praxis-based research networks combine PBRN knowledge generation with multistakeholder learning, experimentation, and application of practical knowledge. The catalytic processes in praxis-based research networks are cycles of action and reflection based on experience, observation, conceptualization, and experimentation by network members and partners. To facilitate co-learning and solution-building, these networks have a flexible architecture that allows pragmatic inclusion of stakeholders based on the demands of the problem and the needs of the network. Praxis-based research networks represent an evolving trend that combines the core values of PBRNs with new opportunities for relevance, rigor, and broad participation. © Copyright 2014 by the American Board of Family Medicine.

Recruitment of participants through community pharmacies for a pharmacogenetic study of antihypertensive drug treatment.

PubMed

van Wieren-de Wijer, Diane B M A; Maitland-van der Zee, Anke-Hilse; de Boer, Anthonius; Stricker, Bruno H Ch; Kroon, Abraham A; de Leeuw, Peter W; Bozkurt, O; Klungel, Olaf H

2009-04-01

To describe the design, recruitment and baseline characteristics of participants in a community pharmacy based pharmacogenetic study of antihypertensive drug treatment. Participants enrolled from the population-based Pharmaco-Morbidity Record Linkage System. We designed a nested case-control study in which we will assess whether specific genetic polymorphisms modify the effect of antihypertensive drugs on the risk of myocardial infarction. In this study, cases (myocardial infarction) and controls were recruited through community pharmacies that participate in PHARMO. The PHARMO database comprises drug dispensing histories of about 2,000,000 subjects from a representative sample of Dutch community pharmacies linked to the national registrations of hospital discharges. In total we selected 31010 patients (2777 cases and 28233 controls) from the PHARMO database, of whom 15973 (1871 cases, 14102 controls) were approached through their community pharmacy. Overall response rate was 36.3% (n = 5791, 794 cases, 4997 controls), whereas 32.1% (n = 5126, 701 cases, 4425 controls) gave informed consent to genotype their DNA. As expected, several cardiovascular risk factors such as smoking, body mass index, hypercholesterolemia, and diabetes mellitus were more common in cases than in controls. Furthermore, cases more often used beta-blockers and calcium-antagonists, whereas controls more often used thiazide diuretics, ACE-inhibitors, and angiotensin-II receptor blockers. We have demonstrated that it is feasible to select patients from a coded database for a pharmacogenetic study and to approach them through community pharmacies, achieving reasonable response rates and without violating privacy rules.

Pharmacogenetics and Metabolism from Science to Implementation in Clinical Practice: The Example of Dihydropyrimidine Dehydrogenase.

PubMed

Del Re, Marzia; Restante, Giuliana; Di Paolo, Antonello; Crucitta, Stefania; Rofi, Eleonora; Danesi, Romano

2017-01-01

Fluoropyrimidines are widely used in the treatment of solid tumors and remain the backbone of many combination chemotherapy regimens. Despite their clinical benefit, they are associated with frequent gastrointestinal and hematological toxicities, which often lead to treatment discontinuation. Fluoropyrimidines undergo complex anabolic and catabolic biotransformation. Enzymes involved in this pathway include dihydropyrimidine dehydrogenase (DPD), which breaks down 5-FU and its prodrugs. Candidate gene approaches have demonstrated associations between 5-FU treatment outcomes and germline polymorphisms in DPD. The aim of this review is to report and discuss the latest results on fluoropyrimidine pharmacogenetics. Literature from PubMed databases and bibliography from retrieved publications have been analyzed according to terms such DPD, DPYD, fluoropyrimdines, polymorphisms, toxicity, pharmacogenetics. To date, many sequence variations have been identified within DPYD gene, although the majority of these have no functional consequences on enzymatic activity. Nowadays, there is a general agreement on the clinical significance of the importance of DPD deficiency in patients who suffer from severe, life-threatening drug toxicity although preemptive testing is not applied to all patients. Considering the published literature, clinicians are strongly encouraged to consider testing for DPD poor metabolizer variants as a rational pre-treatment screening for patients candidate to a fluoropyrimidine-based regimens, in order to prevent toxicities and personalise treatments. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

The prevention research centers' managing epilepsy well network.

PubMed

DiIorio, Colleen K; Bamps, Yvan A; Edwards, Ariele L; Escoffery, Cam; Thompson, Nancy J; Begley, Charles E; Shegog, Ross; Clark, Noreen M; Selwa, Linda; Stoll, Shelley C; Fraser, Robert T; Ciechanowski, Paul; Johnson, Erica K; Kobau, Rosemarie; Price, Patricia H

2010-11-01

The Managing Epilepsy Well (MEW) Network was created in 2007 by the Centers for Disease Control and Prevention's (CDC) Prevention Research Centers and Epilepsy Program to promote epilepsy self-management research and to improve the quality of life for people with epilepsy. MEW Network membership comprises four collaborating centers (Emory University, University of Texas Health Science Center at Houston, University of Michigan, and University of Washington), representatives from CDC, affiliate members, and community stakeholders. This article describes the MEW Network's background, mission statement, research agenda, and structure. Exploratory and intervention studies conducted by individual collaborating centers are described, as are Network collaborative projects, including a multisite depression prevention intervention and the development of a standard measure of epilepsy self-management. Communication strategies and examples of research translation programs are discussed. The conclusion outlines the Network's role in the future development and dissemination of evidence-based epilepsy self-management programs. Copyright © 2010 Elsevier Inc. All rights reserved.

Effects of CYP2D6 Status on Harmaline Metabolism, Pharmacokinetics and Pharmacodynamics, and a Pharmacogenetics-Based Pharmacokinetic Model

PubMed Central

Wu, Chao; Jiang, Xi-Ling; Shen, Hong-Wu; Yu, Ai-Ming

2009-01-01

Harmaline is a β-carboline alkaloid showing neuroprotective and neurotoxic properties. Our recent studies have revealed an important role for cytochrome P450 2D6 (CYP2D6) in harmaline O-demethylation. This study, therefore, aimed to delineate the effects of CYP2D6 phenotype/genotype on harmaline metabolism, pharmacokinetics (PK) and pharmacodynamics (PD), and to develop a pharmacogenetics mechanism-based compartmental PK model. In vitro kinetic studies on metabolite formation in human CYP2D6 extensive metabolizer (EM) and poor metabolizer (PM) hepatocytes indicated that harmaline O-demethylase activity (Vmax/Km) was about 9-fold higher in EM hepatocytes. Substrate depletion showed mono-exponential decay trait, and estimated in vitro harmaline clearance (CLint, μL/min/106 cells) was significantly lower in PM hepatocytes (28.5) than EM hepatocytes (71.1). In vivo studies in CYP2D6-humanized and wild-type mouse models showed that wild-type mice were subjected to higher and longer exposure to harmaline (5 and 15 mg/kg; i.v. and i.p.), and more severe hypothermic responses. The PK/PD data were nicely described by our pharmacogenetics-based PK model involving the clearance of drug by CYP2D6 (CLCYP2D6) and other mechanisms (CLother), and an indirect response PD model, respectively. Wild-type mice were also more sensitive to harmaline in marble-burying tests, as manifested by significantly lower ED50 and steeper Hill slope. These findings suggest that distinct CYP2D6 status may cause considerable variations in harmaline metabolism, PK and PD. In addition, the pharmacogenetics-based PK model may be extended to define PK difference caused by other polymorphic drug-metabolizing enzyme in different populations. PMID:19445902

Increasing Scalability of Researcher Network Extraction from the Web

NASA Astrophysics Data System (ADS)

Asada, Yohei; Matsuo, Yutaka; Ishizuka, Mitsuru

Social networks, which describe relations among people or organizations as a network, have recently attracted attention. With the help of a social network, we can analyze the structure of a community and thereby promote efficient communications within it. We investigate the problem of extracting a network of researchers from the Web, to assist efficient cooperation among researchers. Our method uses a search engine to get the cooccurences of names of two researchers and calculates the streangth of the relation between them. Then we label the relation by analyzing the Web pages in which these two names cooccur. Research on social network extraction using search engines as ours, is attracting attention in Japan as well as abroad. However, the former approaches issue too many queries to search engines to extract a large-scale network. In this paper, we propose a method to filter superfluous queries and facilitates the extraction of large-scale networks. By this method we are able to extract a network of around 3000-nodes. Our experimental results show that the proposed method reduces the number of queries significantly while preserving the quality of the network as compared to former methods.

The APA and the Rise of Pediatric Generalist Network Research

PubMed Central

Wasserman, Richard; Serwint, Janet R.; Kuppermann, Nathan; Srivastava, Rajendu; Dreyer, Benard

2010-01-01

The Academic Pediatric Association (APA – formerly the Ambulatory Pediatric Association) first encouraged multi-institutional collaborative research among its members over thirty years ago. Individual APA members went on subsequently to figure prominently in establishing formal research networks. These enduring collaborations have been established to conduct investigations in a variety of generalist contexts. At present, four generalist networks – Pediatric Research in Office Settings (PROS), the Pediatric Emergency Care Applied Network (PECARN), the COntinuity Research NETwork (CORNET), and Pediatric Research in Inpatient Settings (PRIS) – have a track record of extensive achievement in generating new knowledge aimed at improving the health and health care of children. This review details the history, accomplishments, and future directions of these networks and summarizes the common themes, strengths, challenges and opportunities inherent in pediatric generalist network research. PMID:21282083

Action Research Networks: Role and Purpose in the Evaluation of Research Outcomes and Impacts

ERIC Educational Resources Information Center

Zornes, Deborah; Ferkins, Lesley; Piggot-Irvine, Eileen

2016-01-01

The focus of this paper is to share thinking about networks in action research (AR) and to consider their role, purpose, and how networks' outcomes and impacts might be evaluated. Networks are often a by-product of AR projects, yet research focused on the network itself as part of a project is rare. The paper is one of several associated with the…

Pharmacogenetics in neuroendocrine tumors of the pancreas.

PubMed

Rizvi, Syed Mujtaba; Wong, Joyce; Saif, Muhammad Wasif; Jia, Yuxia

2014-07-28

Neuroendocrine tumors (NETs) arise from cells distributed throughout the endocrine system. Although, NETs are heterogeneous in their behavior, they tend to be more aggressive when arising in the pancreas. Pancreatic NET (panNET) represents three percent of all primary pancreatic neoplasms. Symptomatic and progressive panNETs are generally treated with cytotoxic chemotherapy, whereas molecular targeted therapy is used for nonfunctional tumors without aggressive features. Pharmacogenetics has increasingly been used recently to better identify potential targets for therapy and help select patient-specific therapy. In this review, we discuss two abstracts (Abstracts #4113 and #e15169) presented at the ASCO Annual Meeting in Chicago this year, outlining the potential role of tumor gene and gene product profiling in disease management. We describe what is known about the pathogenesis of these tumors, role of decreased gene product expression (MGMT, RRM1, MET) and its application in cytotoxic therapy selection, as well as genetic mutations that can be used for molecular targeted therapy. With an overall shift towards personalized medicine, it has become ever more important to identify the molecular signature of a tumor as it appears to dictate the clinical behavior and response to therapy.

Research Networks and Technology Migration (RESNETSII)

DTIC Science & Technology

2004-07-01

Laboratory (LBNL), The International Computer Science Institute (ICSI) Center for Internet Research (ICIR) DARWIN Developing protocols and...degradation in network loss, delay and throughput AT&T Center for Internet Research at ICSI (ACIRI), AT&T Labs-Research, University Of Massachusetts

Asian Network of Research Resource Centers.

PubMed

Lee, Sunhee; Nam, Seungjoo; Jung, Paul E; Kim, Ki-Jeong; Lee, Yeonhee

2016-10-01

With the enactment of the Nagoya Protocol, biological resources are now increasingly considered as assets of an individual country, instead of as the common property of mankind. As worldwide interest for securing biological resources intensifies, research resource centers (RRCs), which collect, preserve, and provide resources and their information to academia and industries, are gathering more attention. The Asian Network of Research Resource Centers (ANRRC) strives for conservation and effective use of bioresources and their data by connecting resource centers of Asia, a continent with the greatest diversity of life. Since its foundation in 2009, the Network has significantly expanded to encompass 103 RRCs of 14 countries. Through the Network, member countries discuss opportunities for resource exchange and research collaboration and share biobanking information and regulations of different countries for international harmonization of resource management. ANRRC also contributes to developing of International Standards of biobanks and biological resources as a liaison to the International Organization for Standardization technical committee 276 Biotechnology.

Comparative-effectiveness research in distributed health data networks.

PubMed

Toh, S; Platt, R; Steiner, J F; Brown, J S

2011-12-01

Comparative-effectiveness research (CER) can be conducted within a distributed health data network. Such networks allow secure access to separate data sets from different data partners and overcome many practical obstacles related to patient privacy, data security, and proprietary concerns. A scalable network architecture supports a wide range of CER activities and meets the data infrastructure needs envisioned by the Federal Coordinating Council for Comparative Effectiveness Research.

Social network analysis: Presenting an underused method for nursing research.

PubMed

Parnell, James Michael; Robinson, Jennifer C

2018-06-01

This paper introduces social network analysis as a versatile method with many applications in nursing research. Social networks have been studied for years in many social science fields. The methods continue to advance but remain unknown to most nursing scholars. Discussion paper. English language and interpreted literature was searched from Ovid Healthstar, CINAHL, PubMed Central, Scopus and hard copy texts from 1965 - 2017. Social network analysis first emerged in nursing literature in 1995 and appears minimally through present day. To convey the versatility and applicability of social network analysis in nursing, hypothetical scenarios are presented. The scenarios are illustrative of three approaches to social network analysis and include key elements of social network research design. The methods of social network analysis are underused in nursing research, primarily because they are unknown to most scholars. However, there is methodological flexibility and epistemological versatility capable of supporting quantitative and qualitative research. The analytic techniques of social network analysis can add new insight into many areas of nursing inquiry, especially those influenced by cultural norms. Furthermore, visualization techniques associated with social network analysis can be used to generate new hypotheses. Social network analysis can potentially uncover findings not accessible through methods commonly used in nursing research. Social networks can be analysed based on individual-level attributes, whole networks and subgroups within networks. Computations derived from social network analysis may stand alone to answer a research question or incorporated as variables into robust statistical models. © 2018 John Wiley & Sons Ltd.

When is Pharmacogenetic Testing for Antidepressant Response Ready for the Clinic? A Cost-effectiveness Analysis Based on Data from the STAR*D Study

PubMed Central

Perlis, Roy H.; Patrick, Amanda; Smoller, Jordan W.; Wang, Philip S.

2009-01-01

The potential of personalized medicine to transform the treatment of mood disorders has been widely touted in psychiatry, but has not been quantified. We estimated the costs and benefits of a putative pharmacogenetic test for antidepressant response in the treatment of major depressive disorder (MDD) from the societal perspective. Specifically, we performed cost-effectiveness analyses using state-transition probability models incorporating probabilities from the multicenter STAR*D effectiveness study of MDD. Costs and quality-adjusted life years were compared for sequential antidepressant trials, with or without guidance from a pharmacogenetic test for differential response to selective serotonin reuptake inhibitors (SSRIs). Likely SSRI responders received an SSRI, while likely nonresponders received the norepinephrine/dopamine reuptake inhibitor bupropion. For a 40-year-old with major depressive disorder, applying the pharmacogenetic test and using the non-SSRI bupropion for those at higher risk for nonresponse cost $93,520 per additional quality-adjusted life-year (QALY) compared with treating all patients with an SSRI first and switching sequentially in the case of nonremission. Cost/QALY dropped below $50,000 for tests with remission rate ratios as low as 1.5, corresponding to odds ratios ~1.8–2.0. Tests for differential antidepressant response could thus become cost-effective under certain circumstances. These circumstances, particularly availability of alternative treatment strategies and test effect sizes, can be estimated and should be considered before these tests are broadly applied in clinical settings. PMID:19494805

Comprehensive Oncologic Emergencies Research Network (CONCERN)

Cancer.gov

The Comprehensive Oncologic Emergencies Research Network (CONCERN) was established in March 2015 with the goal to accelerate knowledge generation, synthesis and translation of oncologic emergency medicine research through multi-center collaborations.

Privacy Issues of a National Research and Education Network.

ERIC Educational Resources Information Center

Katz, James E.; Graveman, Richard F.

1991-01-01

Discussion of the right to privacy of communications focuses on privacy expectations within a National Research and Education Network (NREN). Highlights include privacy needs in scientific and education communications; academic and research networks; network security and privacy concerns; protection strategies; and consequences of privacy…

Biological and Environmental Research Network Requirements

DOE Office of Scientific and Technical Information (OSTI.GOV)

Balaji, V.; Boden, Tom; Cowley, Dave

2013-09-01

The Energy Sciences Network (ESnet) is the primary provider of network connectivity for the U.S. Department of Energy (DOE) Office of Science (SC), the single largest supporter of basic research in the physical sciences in the United States. In support of SC programs, ESnet regularly updates and refreshes its understanding of the networking requirements of the instruments, facilities, scientists, and science programs that it serves. This focus has helped ESnet be a highly successful enabler of scientific discovery for over 25 years. In November 2012, ESnet and the Office of Biological and Environmental Research (BER) of the DOE SC organizedmore » a review to characterize the networking requirements of the programs funded by the BER program office. Several key findings resulted from the review. Among them: 1) The scale of data sets available to science collaborations continues to increase exponentially. This has broad impact, both on the network and on the computational and storage systems connected to the network. 2) Many science collaborations require assistance to cope with the systems and network engineering challenges inherent in managing the rapid growth in data scale. 3) Several science domains operate distributed facilities that rely on high-performance networking for success. Key examples illustrated in this report include the Earth System Grid Federation (ESGF) and the Systems Biology Knowledgebase (KBase). This report expands on these points, and addresses others as well. The report contains a findings section as well as the text of the case studies discussed at the review.« less

The Healthy Aging Research Network: Modeling Collaboration for Community Impact.

PubMed

Belza, Basia; Altpeter, Mary; Smith, Matthew Lee; Ory, Marcia G

2017-03-01

As the first Centers for Disease Control and Prevention (CDC) Prevention Research Centers Program thematic network, the Healthy Aging Research Network was established to better understand the determinants of healthy aging within older adult populations, identify interventions that promote healthy aging, and assist in translating research into sustainable community-based programs throughout the nation. To achieve these goals requires concerted efforts of a collaborative network of academic, community, and public health organizational partnerships. For the 2001-2014 Prevention Research Center funding cycles, the Healthy Aging Research Network conducted prevention research and promoted the wide use of practices known to foster optimal health. Organized around components necessary for successful collaborations (i.e., governance and infrastructure, shaping focus, community involvement, and evaluation and improvement), this commentary highlights exemplars that demonstrate the Healthy Aging Research Network's unique contributions to the field. The Healthy Aging Research Network's collaboration provided a means to collectively build capacity for practice and policy, reduce fragmentation and duplication in health promotion and aging research efforts, maximize the efficient use of existing resources and generate additional resources, and ultimately, create synergies for advancing the healthy aging agenda. This collaborative model was built upon a backbone organization (coordinating center); setting of common agendas and mutually reinforcing activities; and continuous communications. Given its successes, the Healthy Aging Research Network model could be used to create new and evaluate existing thematic networks to guide the translation of research into policy and practice. Copyright © 2016 American Journal of Preventive Medicine. Published by Elsevier Inc. All rights reserved.

Research collaboration in groups and networks: differences across academic fields.

PubMed

Kyvik, Svein; Reymert, Ingvild

2017-01-01

The purpose of this paper is to give a macro-picture of collaboration in research groups and networks across all academic fields in Norwegian research universities, and to examine the relative importance of membership in groups and networks for individual publication output. To our knowledge, this is a new approach, which may provide valuable information on collaborative patterns in a particular national system, but of clear relevance to other national university systems. At the system level, conducting research in groups and networks are equally important, but there are large differences between academic fields. The research group is clearly most important in the field of medicine and health, while undertaking research in an international network is most important in the natural sciences. Membership in a research group and active participation in international networks are likely to enhance publication productivity and the quality of research.

US computer research networks: Domestic and international telecommunications capacity requirements

NASA Technical Reports Server (NTRS)

Kratochvil, D.; Sood, D.

1990-01-01

The future telecommunications capacity and connectivity requirements of the United States (US) research and development (R&D) community raise two concerns. First, would there be adequate privately-owned communications capacity to meet the ever-increasing requirements of the US R&D community for domestic and international connectivity? Second, is the method of piecemeal implementation of communications facilities by individual researchers cost effective when viewed from an integrated perspective? To address the capacity issue, Contel recently completed a study for NASA identifying the current domestic R&D telecommunications capacity and connectivity requirements, and projecting the same to the years 1991, 1996, 2000, and 2010. The work reported here extends the scope of an earlier study by factoring in the impact of international connectivity requirements on capacity and connectivity forecasts. Most researchers in foreign countries, as is the case with US researchers, rely on regional, national or continent-wide networks to collaborate with each other, and their US counterparts. The US researchers' international connectivity requirements, therefore, stem from the need to link the US domestic research networks to foreign research networks. The number of links and, more importantly, the speeds of links are invariably determined by the characteristics of the networks being linked. The major thrust of this study, therefore, was to identify and characterize the foreign research networks, to quantify the current status of their connectivity to the US networks, and to project growth in the connectivity requirements to years 1991, 1996, 2000, and 2010 so that a composite picture of the US research networks in the same years could be forecasted. The current (1990) US integrated research network, and its connectivity to foreign research networks is shown. As an example of projections, the same for the year 2010 is shown.

The Impact of the Physical Activity Policy Research Network.

PubMed

Manteiga, Alicia M; Eyler, Amy A; Valko, Cheryl; Brownson, Ross C; Evenson, Kelly R; Schmid, Thomas

2017-03-01

Lack of physical activity is one of the greatest challenges of the 21st century. The Physical Activity Policy Research Network (PAPRN) is a thematic network established in 2004 to identify determinants, implementation, and outcomes of policies that are effective in increasing physical activity. The purpose of this study is to describe the products of PAPRN and make recommendations for future research and best practices. A mixed methods approach was used to obtain both quantitative and qualitative data on the network. First, in 2014, PAPRN's dissemination products from 2004 to 2014 were extracted and reviewed, including 57 publications and 56 presentations. Next, semi-structured qualitative interviews were conducted with 25 key network participants from 17 locations around the U.S. The transcripts were transcribed and coded. The results of the interviews indicated that the research network addressed several components of its mission, including the identification of physical activity policies, determinants of these policies, and the process of policy implementation. However, research focusing on physical activity policy outcomes was limited. Best practices included collaboration between researchers and practitioners and involvement of practitioners in research design, data collection, and dissemination of results. PAPRN is an example of a productive research network and has contributed to both the process and content of physical activity policy research over the past decade. Future research should emphasize physical activity policy outcomes. Additionally, increased partnerships with practitioners for collaborative, cross-sectoral physical activity policy research should be developed. Copyright © 2016 American Journal of Preventive Medicine. All rights reserved.

Building research infrastructure in community health centers: a Community Health Applied Research Network (CHARN) report.

PubMed

Likumahuwa, Sonja; Song, Hui; Singal, Robbie; Weir, Rosy Chang; Crane, Heidi; Muench, John; Sim, Shao-Chee; DeVoe, Jennifer E

2013-01-01

This article introduces the Community Health Applied Research Network (CHARN), a practice-based research network of community health centers (CHCs). Established by the Health Resources and Services Administration in 2010, CHARN is a network of 4 community research nodes, each with multiple affiliated CHCs and an academic center. The four nodes (18 individual CHCs and 4 academic partners in 9 states) are supported by a data coordinating center. Here we provide case studies detailing how CHARN is building research infrastructure and capacity in CHCs, with a particular focus on how community practice-academic partnerships were facilitated by the CHARN structure. The examples provided by the CHARN nodes include many of the building blocks of research capacity: communication capacity and "matchmaking" between providers and researchers; technology transfer; research methods tailored to community practice settings; and community institutional review board infrastructure to enable community oversight. We draw lessons learned from these case studies that we hope will serve as examples for other networks, with special relevance for community-based networks seeking to build research infrastructure in primary care settings.

Building Research Infrastructure in Community Health Centers: A Community Health Applied Research Network (CHARN) Report

PubMed Central

Likumahuwa, Sonja; Song, Hui; Singal, Robbie; Weir, Rosy Chang; Crane, Heidi; Muench, John; Sim, Shao-Chee; DeVoe, Jennifer E.

2015-01-01

This article introduces the Community Health Applied Research Network (CHARN), a practice-based research network of community health centers (CHCs). Established by the Health Resources and Services Administration in 2010, CHARN is a network of 4 community research nodes, each with multiple affiliated CHCs and an academic center. The four nodes (18 individual CHCs and 4 academic partners in 9 states) are supported by a data coordinating center. Here we provide case studies detailing how CHARN is building research infrastructure and capacity in CHCs, with a particular focus on how community practice-academic partnerships were facilitated by the CHARN structure. The examples provided by the CHARN nodes include many of the building blocks of research capacity: communication capacity and “matchmaking” between providers and researchers; technology transfer; research methods tailored to community practice settings; and community institutional review board infrastructure to enable community oversight. We draw lessons learned from these case studies that we hope will serve as examples for other networks, with special relevance for community-based networks seeking to build research infrastructure in primary care settings. PMID:24004710

Identifying emerging research collaborations and networks: method development.

PubMed

Dozier, Ann M; Martina, Camille A; O'Dell, Nicole L; Fogg, Thomas T; Lurie, Stephen J; Rubinstein, Eric P; Pearson, Thomas A

2014-03-01

Clinical and translational research is a multidisciplinary, collaborative team process. To evaluate this process, we developed a method to document emerging research networks and collaborations in our medical center to describe their productivity and viability over time. Using an e-mail survey, sent to 1,620 clinical and basic science full- and part-time faculty members, respondents identified their research collaborators. Initial analyses, using Pajek software, assessed the feasibility of using social network analysis (SNA) methods with these data. Nearly 400 respondents identified 1,594 collaborators across 28 medical center departments resulting in 309 networks with 5 or more collaborators. This low-burden approach yielded a rich data set useful for evaluation using SNA to: (a) assess networks at several levels of the organization, including intrapersonal (individuals), interpersonal (social), organizational/institutional leadership (tenure and promotion), and physical/environmental (spatial proximity) and (b) link with other data to assess the evolution of these networks.

Constructing of Research-Oriented Learning Mode Based on Network Environment

ERIC Educational Resources Information Center

Wang, Ying; Li, Bing; Xie, Bai-zhi

2007-01-01

Research-oriented learning mode that based on network is significant to cultivate comprehensive-developing innovative person with network teaching in education for all-around development. This paper establishes a research-oriented learning mode by aiming at the problems existing in research-oriented learning based on network environment, and…

[Cooperative Cardiovascular Disease Research Network (RECAVA)].

PubMed

García-Dorado, David; Castro-Beiras, Alfonso; Díez, Javier; Gabriel, Rafael; Gimeno-Blanes, Juan R; Ortiz de Landázuri, Manuel; Sánchez, Pedro L; Fernández-Avilés, Francisco

2008-01-01

Today, cardiovascular disease is the principal cause of death and hospitalization in Spain, and accounts for an annual healthcare budget of more than 4000 million euros. Consequently, early diagnosis, effective prevention, and the optimum treatment of cardiovascular disease present a significant social and healthcare challenge for the country. In this context, combining all available resources to increase the efficacy and healthcare benefits of scientific research is a priority. This rationale prompted the establishment of the Spanish Cooperative Cardiovascular Disease Research Network, or RECAVA (Red Temática de Investigación Cooperativa en Enfermedades Cardiovasculares), 5 years ago. Since its foundation, RECAVA's activities have focused on achieving four objectives: a) to facilitate contacts between basic, clinical and epidemiological researchers; b) to promote the shared use of advanced technological facilities; c) to apply research results to clinical practice, and d) to train a new generation of translational cardiovascular researchers in Spain. At present, RECAVA consists of 41 research groups and seven shared technological facilities. RECAVA's research strategy is based on a scientific design matrix centered on the most important cardiovascular processes. The level of RECAVA's research activity is reflected in the fact that 28 co-authored articles were published in international journals during the first six months of 2007, with each involving contributions from at least two groups in the network. Finally, RECAVA also participates in the work of the Spanish National Center for Cardiovascular Research, or CNIC (Centro Nacional de Investigación Cardiovascular), and some established Biomedical Research Network Centers, or CIBER (Centros de Investigación Biomédica en RED), with the aim of consolidating the development of a dynamic multidisciplinary research framework that is capable of meeting the growing challenge that cardiovascular disease will present

Conceptualizing and Advancing Research Networking Systems

PubMed Central

SCHLEYER, TITUS; BUTLER, BRIAN S.; SONG, MEI; SPALLEK, HEIKO

2013-01-01

Science in general, and biomedical research in particular, is becoming more collaborative. As a result, collaboration with the right individuals, teams, and institutions is increasingly crucial for scientific progress. We propose Research Networking Systems (RNS) as a new type of system designed to help scientists identify and choose collaborators, and suggest a corresponding research agenda. The research agenda covers four areas: foundations, presentation, architecture, and evaluation. Foundations includes project-, institution- and discipline-specific motivational factors; the role of social networks; and impression formation based on information beyond expertise and interests. Presentation addresses representing expertise in a comprehensive and up-to-date manner; the role of controlled vocabularies and folksonomies; the tension between seekers’ need for comprehensive information and potential collaborators’ desire to control how they are seen by others; and the need to support serendipitous discovery of collaborative opportunities. Architecture considers aggregation and synthesis of information from multiple sources, social system interoperability, and integration with the user’s primary work context. Lastly, evaluation focuses on assessment of collaboration decisions, measurement of user-specific costs and benefits, and how the large-scale impact of RNS could be evaluated with longitudinal and naturalistic methods. We hope that this article stimulates the human-computer interaction, computer-supported cooperative work, and related communities to pursue a broad and comprehensive agenda for developing research networking systems. PMID:24376309

Conceptualizing and Advancing Research Networking Systems.

PubMed

Schleyer, Titus; Butler, Brian S; Song, Mei; Spallek, Heiko

2012-03-01

Science in general, and biomedical research in particular, is becoming more collaborative. As a result, collaboration with the right individuals, teams, and institutions is increasingly crucial for scientific progress. We propose Research Networking Systems (RNS) as a new type of system designed to help scientists identify and choose collaborators, and suggest a corresponding research agenda. The research agenda covers four areas: foundations, presentation, architecture , and evaluation . Foundations includes project-, institution- and discipline-specific motivational factors; the role of social networks; and impression formation based on information beyond expertise and interests. Presentation addresses representing expertise in a comprehensive and up-to-date manner; the role of controlled vocabularies and folksonomies; the tension between seekers' need for comprehensive information and potential collaborators' desire to control how they are seen by others; and the need to support serendipitous discovery of collaborative opportunities. Architecture considers aggregation and synthesis of information from multiple sources, social system interoperability, and integration with the user's primary work context. Lastly, evaluation focuses on assessment of collaboration decisions, measurement of user-specific costs and benefits, and how the large-scale impact of RNS could be evaluated with longitudinal and naturalistic methods. We hope that this article stimulates the human-computer interaction, computer-supported cooperative work, and related communities to pursue a broad and comprehensive agenda for developing research networking systems.

Role of Pharmacogenetics in Hematopoietic Stem Cell Transplantation Outcome in Children

PubMed Central

Franca, Raffaella; Stocco, Gabriele; Favretto, Diego; Giurici, Nagua; Decorti, Giuliana; Rabusin, Marco

2015-01-01

Hematopoietic stem cell transplantation (HSCT) is an established therapeutic procedure for several congenital and acquired disorders, both malignant and nonmalignant. Despite the great improvements in HSCT clinical practices over the last few decades, complications, such as graft vs. host disease (GVHD) and sinusoidal obstructive syndrome (SOS), are still largely unpredictable and remain the major causes of morbidity and mortality. Both donor and patient genetic background might influence the success of bone marrow transplantation and could at least partially explain the inter-individual variability in HSCT outcome. This review summarizes some of the recent studies on candidate gene polymorphisms in HSCT, with particular reference to pediatric cohorts. The interest is especially focused on pharmacogenetic variants affecting myeloablative and immunosuppressive drugs, although genetic traits involved in SOS susceptibility and transplant-related mortality are also reviewed. PMID:26266406

The Earth Science Research Network as Seen Through Network Analysis of the AGU

NASA Astrophysics Data System (ADS)

Narock, T.; Hasnain, S.; Stephan, R.

2017-12-01

Scientometrics is the science of science. Scientometric research includes measurements of impact, mapping of scientific fields, and the production of indicators for use in policy and management. We have leveraged network analysis in a scientometric study of the American Geophysical Union (AGU). Data from the AGU's Linked Data Abstract Browser was used to create a visualization and analytics tools to explore the Earth science's research network. Our application applies network theory to look at network structure within the various AGU sections, identify key individuals and communities related to Earth science topics, and examine multi-disciplinary collaboration across sections. Opportunities to optimize Earth science output, as well as policy and outreach applications, are discussed.

Cognitive radio wireless sensor networks: applications, challenges and research trends.

PubMed

Joshi, Gyanendra Prasad; Nam, Seung Yeob; Kim, Sung Won

2013-08-22

A cognitive radio wireless sensor network is one of the candidate areas where cognitive techniques can be used for opportunistic spectrum access. Research in this area is still in its infancy, but it is progressing rapidly. The aim of this study is to classify the existing literature of this fast emerging application area of cognitive radio wireless sensor networks, highlight the key research that has already been undertaken, and indicate open problems. This paper describes the advantages of cognitive radio wireless sensor networks, the difference between ad hoc cognitive radio networks, wireless sensor networks, and cognitive radio wireless sensor networks, potential application areas of cognitive radio wireless sensor networks, challenges and research trend in cognitive radio wireless sensor networks. The sensing schemes suited for cognitive radio wireless sensor networks scenarios are discussed with an emphasis on cooperation and spectrum access methods that ensure the availability of the required QoS. Finally, this paper lists several open research challenges aimed at drawing the attention of the readers toward the important issues that need to be addressed before the vision of completely autonomous cognitive radio wireless sensor networks can be realized.

Cognitive Radio Wireless Sensor Networks: Applications, Challenges and Research Trends

PubMed Central

Joshi, Gyanendra Prasad; Nam, Seung Yeob; Kim, Sung Won

2013-01-01

A cognitive radio wireless sensor network is one of the candidate areas where cognitive techniques can be used for opportunistic spectrum access. Research in this area is still in its infancy, but it is progressing rapidly. The aim of this study is to classify the existing literature of this fast emerging application area of cognitive radio wireless sensor networks, highlight the key research that has already been undertaken, and indicate open problems. This paper describes the advantages of cognitive radio wireless sensor networks, the difference between ad hoc cognitive radio networks, wireless sensor networks, and cognitive radio wireless sensor networks, potential application areas of cognitive radio wireless sensor networks, challenges and research trend in cognitive radio wireless sensor networks. The sensing schemes suited for cognitive radio wireless sensor networks scenarios are discussed with an emphasis on cooperation and spectrum access methods that ensure the availability of the required QoS. Finally, this paper lists several open research challenges aimed at drawing the attention of the readers toward the important issues that need to be addressed before the vision of completely autonomous cognitive radio wireless sensor networks can be realized. PMID:23974152

CollaborationViz: Interactive Visual Exploration of Biomedical Research Collaboration Networks

PubMed Central

Bian, Jiang; Xie, Mengjun; Hudson, Teresa J.; Eswaran, Hari; Brochhausen, Mathias; Hanna, Josh; Hogan, William R.

2014-01-01

Social network analysis (SNA) helps us understand patterns of interaction between social entities. A number of SNA studies have shed light on the characteristics of research collaboration networks (RCNs). Especially, in the Clinical Translational Science Award (CTSA) community, SNA provides us a set of effective tools to quantitatively assess research collaborations and the impact of CTSA. However, descriptive network statistics are difficult for non-experts to understand. In this article, we present our experiences of building meaningful network visualizations to facilitate a series of visual analysis tasks. The basis of our design is multidimensional, visual aggregation of network dynamics. The resulting visualizations can help uncover hidden structures in the networks, elicit new observations of the network dynamics, compare different investigators and investigator groups, determine critical factors to the network evolution, and help direct further analyses. We applied our visualization techniques to explore the biomedical RCNs at the University of Arkansas for Medical Sciences – a CTSA institution. And, we created CollaborationViz, an open-source visual analytical tool to help network researchers and administration apprehend the network dynamics of research collaborations through interactive visualization. PMID:25405477

The Evolution of the Personal Networks of Novice Librarian Researchers

ERIC Educational Resources Information Center

Kennedy, Marie R.; Kennedy, David P.; Brancolini, Kristine R.

2017-01-01

This article describes for the first time the composition and structure of the personal networks of novice librarian researchers. We used social network analysis to observe if participating in the Institute for Research Design in Librarianship (IRDL) affected the development of the librarians' personal networks and how the networks changed over…

Direct2Experts: a pilot national network to demonstrate interoperability among research-networking platforms.

PubMed

Weber, Griffin M; Barnett, William; Conlon, Mike; Eichmann, David; Kibbe, Warren; Falk-Krzesinski, Holly; Halaas, Michael; Johnson, Layne; Meeks, Eric; Mitchell, Donald; Schleyer, Titus; Stallings, Sarah; Warden, Michael; Kahlon, Maninder

2011-12-01

Research-networking tools use data-mining and social networking to enable expertise discovery, matchmaking and collaboration, which are important facets of team science and translational research. Several commercial and academic platforms have been built, and many institutions have deployed these products to help their investigators find local collaborators. Recent studies, though, have shown the growing importance of multiuniversity teams in science. Unfortunately, the lack of a standard data-exchange model and resistance of universities to share information about their faculty have presented barriers to forming an institutionally supported national network. This case report describes an initiative, which, in only 6 months, achieved interoperability among seven major research-networking products at 28 universities by taking an approach that focused on addressing institutional concerns and encouraging their participation. With this necessary groundwork in place, the second phase of this effort can begin, which will expand the network's functionality and focus on the end users.

Direct2Experts: a pilot national network to demonstrate interoperability among research-networking platforms

PubMed Central

Barnett, William; Conlon, Mike; Eichmann, David; Kibbe, Warren; Falk-Krzesinski, Holly; Halaas, Michael; Johnson, Layne; Meeks, Eric; Mitchell, Donald; Schleyer, Titus; Stallings, Sarah; Warden, Michael; Kahlon, Maninder

2011-01-01

Research-networking tools use data-mining and social networking to enable expertise discovery, matchmaking and collaboration, which are important facets of team science and translational research. Several commercial and academic platforms have been built, and many institutions have deployed these products to help their investigators find local collaborators. Recent studies, though, have shown the growing importance of multiuniversity teams in science. Unfortunately, the lack of a standard data-exchange model and resistance of universities to share information about their faculty have presented barriers to forming an institutionally supported national network. This case report describes an initiative, which, in only 6 months, achieved interoperability among seven major research-networking products at 28 universities by taking an approach that focused on addressing institutional concerns and encouraging their participation. With this necessary groundwork in place, the second phase of this effort can begin, which will expand the network's functionality and focus on the end users. PMID:22037890

Advanced Scientific Computing Research Network Requirements: ASCR Network Requirements Review Final Report

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bacon, Charles; Bell, Greg; Canon, Shane

The Energy Sciences Network (ESnet) is the primary provider of network connectivity for the U.S. Department of Energy (DOE) Office of Science (SC), the single largest supporter of basic research in the physical sciences in the United States. In support of SC programs, ESnet regularly updates and refreshes its understanding of the networking requirements of the instruments, facilities, scientists, and science programs that it serves. This focus has helped ESnet to be a highly successful enabler of scientific discovery for over 25 years. In October 2012, ESnet and the Office of Advanced Scientific Computing Research (ASCR) of the DOE SCmore » organized a review to characterize the networking requirements of the programs funded by the ASCR program office. The requirements identified at the review are summarized in the Findings section, and are described in more detail in the body of the report.« less

Pharmacogenetics of drug-drug interaction and drug-drug-gene interaction: a systematic review on CYP2C9, CYP2C19 and CYP2D6.

PubMed

Bahar, Muh Akbar; Setiawan, Didik; Hak, Eelko; Wilffert, Bob

2017-05-01

Currently, most guidelines on drug-drug interaction (DDI) neither consider the potential effect of genetic polymorphism in the strength of the interaction nor do they account for the complex interaction caused by the combination of DDI and drug-gene interaction (DGI) where there are multiple biotransformation pathways, which is referred to as drug-drug-gene interaction (DDGI). In this systematic review, we report the impact of pharmacogenetics on DDI and DDGI in which three major drug-metabolizing enzymes - CYP2C9, CYP2C19 and CYP2D6 - are central. We observed that several DDI and DDGI are highly gene-dependent, leading to a different magnitude of interaction. Precision drug therapy should take pharmacogenetics into account when drug interactions in clinical practice are expected.

Enabling Research Network Connectivity to Clouds with Virtual Router Technology

NASA Astrophysics Data System (ADS)

Seuster, R.; Casteels, K.; Leavett-Brown, CR; Paterson, M.; Sobie, RJ

2017-10-01

The use of opportunistic cloud resources by HEP experiments has significantly increased over the past few years. Clouds that are owned or managed by the HEP community are connected to the LHCONE network or the research network with global access to HEP computing resources. Private clouds, such as those supported by non-HEP research funds are generally connected to the international research network; however, commercial clouds are either not connected to the research network or only connect to research sites within their national boundaries. Since research network connectivity is a requirement for HEP applications, we need to find a solution that provides a high-speed connection. We are studying a solution with a virtual router that will address the use case when a commercial cloud has research network connectivity in a limited region. In this situation, we host a virtual router in our HEP site and require that all traffic from the commercial site transit through the virtual router. Although this may increase the network path and also the load on the HEP site, it is a workable solution that would enable the use of the remote cloud for low I/O applications. We are exploring some simple open-source solutions. In this paper, we present the results of our studies and how it will benefit our use of private and public clouds for HEP computing.

Co-authorship network analysis in health research: method and potential use.

PubMed

Fonseca, Bruna de Paula Fonseca E; Sampaio, Ricardo Barros; Fonseca, Marcus Vinicius de Araújo; Zicker, Fabio

2016-04-30

Scientific collaboration networks are a hallmark of contemporary academic research. Researchers are no longer independent players, but members of teams that bring together complementary skills and multidisciplinary approaches around common goals. Social network analysis and co-authorship networks are increasingly used as powerful tools to assess collaboration trends and to identify leading scientists and organizations. The analysis reveals the social structure of the networks by identifying actors and their connections. This article reviews the method and potential applications of co-authorship network analysis in health. The basic steps for conducting co-authorship studies in health research are described and common network metrics are presented. The application of the method is exemplified by an overview of the global research network for Chikungunya virus vaccines.

Research and knowledge in Ontario tobacco control networks.

PubMed

Bickford, Julia J; Kothari, Anita R

2008-01-01

This study sought to better understand the role of research knowledge in Ontario tobacco control networks by asking: 1) How is research managed; 2) How is research evaluated; and 3) How is research utilized? This is a secondary analysis of a qualitative study based on individual semistructured interviews with 29 participants between January and May 2006. These participants were purposefully sampled from across four Ministries in the provincial government (n = 7), non-government (n = 15), and public health organizations (n = 7). Interviews were transcribed verbatim and coded and analyzed using QSR N7 qualitative software. This study received ethics approval from The University of Western Ontario Health Research Ethics Board. There exists a dissonance between the preference for peer-reviewed, unbiased, non-partisan knowledge to support claims and the need for fast, "real-time" information on which to base tobacco-related policy decisions. Second, there is a great deal of tacit knowledge held by experts within the Ontario tobacco control community. The networks among government, non-government, and public health organizations are the structures through which tacit knowledge is exchanged. These networks are dynamic, fluid and shifting. There exists a gap in the production and utilization of research knowledge for tobacco control policy. Tacit knowledge held by experts in Ontario tobacco control networks is an integral means of managing and evaluating research knowledge. Finally, this study builds on Weiss's concept of tactical model of evidence use by highlighting the utilization of research to enhance one's credibility.

Detecting and analyzing research communities in longitudinal scientific networks.

PubMed

Leone Sciabolazza, Valerio; Vacca, Raffaele; Kennelly Okraku, Therese; McCarty, Christopher

2017-01-01

A growing body of evidence shows that collaborative teams and communities tend to produce the highest-impact scientific work. This paper proposes a new method to (1) Identify collaborative communities in longitudinal scientific networks, and (2) Evaluate the impact of specific research institutes, services or policies on the interdisciplinary collaboration between these communities. First, we apply community-detection algorithms to cross-sectional scientific collaboration networks and analyze different types of co-membership in the resulting subgroups over time. This analysis summarizes large amounts of longitudinal network data to extract sets of research communities whose members have consistently collaborated or shared collaborators over time. Second, we construct networks of cross-community interactions and estimate Exponential Random Graph Models to predict the formation of interdisciplinary collaborations between different communities. The method is applied to longitudinal data on publication and grant collaborations at the University of Florida. Results show that similar institutional affiliation, spatial proximity, transitivity effects, and use of the same research services predict higher degree of interdisciplinary collaboration between research communities. Our application also illustrates how the identification of research communities in longitudinal data and the analysis of cross-community network formation can be used to measure the growth of interdisciplinary team science at a research university, and to evaluate its association with research policies, services or institutes.

Detecting and analyzing research communities in longitudinal scientific networks

PubMed Central

Vacca, Raffaele; Kennelly Okraku, Therese; McCarty, Christopher

2017-01-01

A growing body of evidence shows that collaborative teams and communities tend to produce the highest-impact scientific work. This paper proposes a new method to (1) Identify collaborative communities in longitudinal scientific networks, and (2) Evaluate the impact of specific research institutes, services or policies on the interdisciplinary collaboration between these communities. First, we apply community-detection algorithms to cross-sectional scientific collaboration networks and analyze different types of co-membership in the resulting subgroups over time. This analysis summarizes large amounts of longitudinal network data to extract sets of research communities whose members have consistently collaborated or shared collaborators over time. Second, we construct networks of cross-community interactions and estimate Exponential Random Graph Models to predict the formation of interdisciplinary collaborations between different communities. The method is applied to longitudinal data on publication and grant collaborations at the University of Florida. Results show that similar institutional affiliation, spatial proximity, transitivity effects, and use of the same research services predict higher degree of interdisciplinary collaboration between research communities. Our application also illustrates how the identification of research communities in longitudinal data and the analysis of cross-community network formation can be used to measure the growth of interdisciplinary team science at a research university, and to evaluate its association with research policies, services or institutes. PMID:28797047

Pharmacogenetics of clozapine response and induced weight gain: A comprehensive review and meta-analysis.

PubMed

Gressier, Florence; Porcelli, Stefano; Calati, Raffaella; Serretti, Alessandro

2016-02-01

Clozapine (CLZ) is the prototype atypical antipsychotic and it has many advantages over other antipsychotic drugs. Several data suggest that both CLZ response and induced weight gain are strongly determined by genetic variability. However, results remain mainly inconclusive. We aim to review the literature data about pharmacogenetics studies on CLZ efficacy, focusing on pharmacodynamic genes. Further, we performed meta-analyses on response when at least three studies for each polymorphism were available. Sensitivity analyses were conducted on Caucasian population when feasible. Electronic literature search was performed to identify pertinent studies published until May 2014 using PubMed, ISI Web of Knowledge and PsycINFO databases. For meta-analyses, data were entered and analyzed through RevMan version 5.2 using a random-effect model. Our literature search yielded 9266 articles on CLZ; among these, we identified 59 pertinent pharmacogenetic studies. Genotype data were retrieved for 14 polymorphisms in 9 genes. Among these, we had available data from at least three independent samples for 8 SNPs in 6 genes to perform meta-analyses: DRD2 rs1799732, DRD3 rs6280, HTR2A rs6313, rs6311, rs6314, HTR2C rs6318, HTR3A rs1062613, TNFa rs1800629. Although literature review provided conflicting results, in meta-analyses three genetic variants within serotonin genes resulted associated to CLZ response: rs6313 and rs6314 within HTR2A gene and rs1062613 within HT3A gene. On the other hand, no clear finding emerged for CLZ-induced weight gain. Our results suggest a possible serotonergic modulation of CLZ clinical response. Copyright © 2015 Elsevier B.V. and ECNP. All rights reserved.

Measuring the impact of practice-based research networks on member dentists in the Collaboration on Networked Dental and Oral Health Research, CONDOR.

PubMed

McBride, Ruth; Leroux, Brian; Lindblad, Anne; Williams, O Dale; Lehmann, Maryann; Rindal, D Brad; Botello-Harbaum, Maria; Gilbert, Gregg H; Gillette, Jane; Demko, Catherine

2013-05-01

The National Institute of Dental and Craniofacial Research funded three practice-based research networks (PBRNs), NW-PRECEDENT, PEARL and DPBRN to conduct studies relevant to practicing general dentists. These PBRNs collaborated to develop a questionnaire to assess the impact of network participation on changes in practice patterns. This report presents results from the initial administration of the questionnaire. Questionnaires were administered to network dentists and a non-network reference group. Practice patterns including caries diagnosis and treatment, pulp cap materials, third molar extraction, dentine hypersensitivity treatments and endodontic treatment and restoration were assessed by network, years in practice, and level of network participation. Test-retest reliability of the questionnaire was evaluated. 950 practitioners completed the questionnaire. Test-retest reliability was good-excellent (kappa>0.4) for most questions. Significant differences in responses by network were not observed. The use of caries risk assessment forms differed by both network participation (p<0.001) and years since dental degree (p=0.026). Recent dental graduates are more likely to recommend third molar removal for preventive reasons (p=0.003). Practitioners in the CONDOR research networks are similar to their US colleagues. As a group, however, these practitioners show a more evidence-based approach to their practice. Dental PBRNs have the potential to improve the translation of evidence into daily practice. Designing methods to assess practice change and the associated factors is essential to addressing this important issue. Copyright © 2013 Elsevier Ltd. All rights reserved.

The Value of Trainee Networks in Pediatric Surgical Research.

PubMed

Skerritt, Clare; Hall, Nigel J

2015-12-01

In 2007, the first trainee-led surgical research network was founded in the United Kingdom (UK). The West Midlands Research Collaborative was started by a group of enthusiastic adult surgical trainees who saw the benefits of altruistic collaboration to generate high quality, multicenter research. Seeing the success of their research projects, including randomized controlled trials, trainees in other regions and specialties were spurred on to founding their own research collaboratives. The Pediatric Surgical Trainee Research Network was started in 2011 by a group of UK trainees with the aim to promote, facilitate, and encourage trainee-led research in pediatric surgery. This article summarizes the history and evolution of the trainee collaborative surgical research. It examines the challenges which multicenter research entails and the steps the collaboratives have taken to overcome them. We describe some of the projects which have been successfully completed and the benefits that the trainee networks have for patients and surgeons alike. Georg Thieme Verlag KG Stuttgart · New York.

Personalized medicine and pharmacogenetic biomarkers: progress in molecular oncology testing

PubMed Central

Ong, Frank S; Das, Kingshuk; Wang, Jay; Vakil, Hana; Kuo, Jane Z; Blackwell, Wendell-Lamar B; Lim, Stephen W; Goodarzi, Mark O; Bernstein, Kenneth E; Rotter, Jerome I; Grody, Wayne W

2012-01-01

In the field of oncology, clinical molecular diagnostics and biomarker discoveries are constantly advancing as the intricate molecular mechanisms that transform a normal cell into an aberrant state in concert with the dysregulation of alternative complementary pathways are increasingly understood. Progress in biomarker technology, coupled with the companion clinical diagnostic laboratory tests, continue to advance this field, where individualized and customized treatment appropriate for each individual patient define the standard of care. Here, we discuss the current commonly used predictive pharmacogenetic biomarkers in clinical oncology molecular testing: BRAF V600E for vemurafenib in melanoma; EML4–ALK for crizotinib and EGFR for erlotinib and gefitinib in non-small-cell lung cancer; KRAS against the use of cetuximab and panitumumab in colorectal cancer; ERBB2 (HER2/neu) for trastuzumab in breast cancer; BCR–ABL for tyrosine kinase inhibitors in chronic myeloid leukemia; and PML/RARα for all-trans-retinoic acid and arsenic trioxide treatment for acute promyelocytic leukemia. PMID:22845480

Collaborative research networks in health: a pragmatic scoping study for the development of an imaging network.

PubMed

Robinson, Tracy Elizabeth; Rankin, Nicole; Janssen, Anna; Mcgregor, Deborah; Grieve, Stuart; Shaw, Timothy

2015-12-09

Collaborative research networks are often touted as a solution for enhancing the translation of knowledge, but questions remain about how to evaluate their impact on health service delivery. This pragmatic scoping study explored the enabling factors for developing and supporting a collaborative imaging network in a metropolitan university in Australia. An advisory group was established to provide governance and to identify key informants and participants. Focus group discussions (n = 2) and semi-structured interviews (n = 22) were facilitated with representatives from a broad range of disciplines. In addition, a survey, a review of relevant websites (n = 15) and a broad review of the literature were undertaken to elicit information on collaborative research networks and perceived needs and factors that would support their involvement in a multi-disciplinary collaborative research network. Findings were de-identified and broad themes were identified. Participants identified human factors as having priority for developing and sustaining a collaborative research network. In particular, leadership, a shared vision and a communication plan that includes social media were identified as crucial for sustaining an imaging network in health research. It is important to develop metrics that map relationships between network members and the role that communication tools can contribute to this process. This study confirms that human factors remain significant across a range of collaborative endeavours. The use of focus group discussions, interviews, and literature and website reviews means we can now strongly recommend the primacy of human factors. More work is needed to identify how the network operates and what specific indicators or metrics help build the capacity of clinicians and scientists to participate in translational research.

Research of Ad Hoc Networks Access Algorithm

NASA Astrophysics Data System (ADS)

Xiang, Ma

With the continuous development of mobile communication technology, Ad Hoc access network has become a hot research, Ad Hoc access network nodes can be used to expand capacity of multi-hop communication range of mobile communication system, even business adjacent to the community, improve edge data rates. When the ad hoc network is the access network of the internet, the gateway discovery protocol is very important to choose the most appropriate gateway to guarantee the connectivity between ad hoc network and IP based fixed networks. The paper proposes a QoS gateway discovery protocol which uses the time delay and stable route to the gateway selection conditions. And according to the gateway discovery protocol, it also proposes a fast handover scheme which can decrease the handover time and improve the handover efficiency.

Is a practice-based rural research network feasible in Europe?

PubMed

Klemenc-Ketis, Zalika; Kurpas, Donata; Tsiligianni, Ioanna; Petrazzuoli, Ferdinando; Jacquet, Jean-Pierre; Buono, Nicola; Lopez-Abuin, Jose; Lionis, Christos

2015-01-01

Research in family medicine is a well-established entity nationally and internationally, covering all aspects of primary care including remote and isolated practices. However, due to limited capacity and resources in rural family medicine, its potential is not fully exploited yet. An idea to foster European rural primary care research by establishing a practice-based research network has been recently put forward by several members of the European Rural and Isolated Practitioners Association (EURIPA) and the European General Practice Research Network (EGPRN). Two workshops on why, and how to design a practice-based research network among rural family practices in Europe were conducted at two international meetings. This paper revisits the definition of practice-based research in family medicine, reflects on the current situation in Europe regarding the research in rural family practice, and discusses a rationale for practice-based research in rural family medicine. A SWOT analysis was used as the main tool to analyse the current situation in Europe regarding the research in rural family practice at both meetings. The key messages gained from these meetings may be employed by the Wonca Working Party on research, the International Federation of Primary Care Research Network and the EGPRN that seek to introduce a practice-based research approach. The cooperation and collaboration between EURIPA and EGPRN creates a fertile ground to discuss further the prospect of a European practice-based rural family medicine research network, and to draw on the joint experience.

Research on key technology of space laser communication network

NASA Astrophysics Data System (ADS)

Chang, Chengwu; Huang, Huiming; Liu, Hongyang; Gao, Shenghua; Cheng, Liyu

2016-10-01

Since the 21st century, Spatial laser communication has made a breakthrough development. Europe, the United States, Japan and other space powers have carried out the test of spatial laser communication technology on-orbit, and put forward a series of plans. In 2011, China made the first technology demonstration of satellite-ground laser communication carried by HY-2 satellite. Nowadays, in order to improve the transmission rate of spatial network, the topic of spatial laser communication network is becoming a research hotspot at home and abroad. This thesis, from the basic problem of spatial laser communication network to solve, analyzes the main difference between spatial network and ground network, which draws forth the key technology of spatial laser communication backbone network, and systematically introduces our research on aggregation, addressing, architecture of spatial network. From the perspective of technology development status and trends, the thesis proposes the development route of spatial laser communication network in stages. So as to provide reference about the development of spatial laser communication network in China.

Pharmacogenetic-guided dosing of coumarin anticoagulants: algorithms for warfarin, acenocoumarol and phenprocoumon

PubMed Central

Verhoef, Talitha I; Redekop, William K; Daly, Ann K; van Schie, Rianne M F; de Boer, Anthonius; Maitland-van der Zee, Anke-Hilse

2014-01-01

Coumarin derivatives, such as warfarin, acenocoumarol and phenprocoumon are frequently prescribed oral anticoagulants to treat and prevent thromboembolism. Because there is a large inter-individual and intra-individual variability in dose–response and a small therapeutic window, treatment with coumarin derivatives is challenging. Certain polymorphisms in CYP2C9 and VKORC1 are associated with lower dose requirements and a higher risk of bleeding. In this review we describe the use of different coumarin derivatives, pharmacokinetic characteristics of these drugs and differences amongst the coumarins. We also describe the current clinical challenges and the role of pharmacogenetic factors. These genetic factors are used to develop dosing algorithms and can be used to predict the right coumarin dose. The effectiveness of this new dosing strategy is currently being investigated in clinical trials. PMID:23919835

pSCANNER: patient-centered Scalable National Network for Effectiveness Research

PubMed Central

Ohno-Machado, Lucila; Agha, Zia; Bell, Douglas S; Dahm, Lisa; Day, Michele E; Doctor, Jason N; Gabriel, Davera; Kahlon, Maninder K; Kim, Katherine K; Hogarth, Michael; Matheny, Michael E; Meeker, Daniella; Nebeker, Jonathan R

2014-01-01

This article describes the patient-centered Scalable National Network for Effectiveness Research (pSCANNER), which is part of the recently formed PCORnet, a national network composed of learning healthcare systems and patient-powered research networks funded by the Patient Centered Outcomes Research Institute (PCORI). It is designed to be a stakeholder-governed federated network that uses a distributed architecture to integrate data from three existing networks covering over 21 million patients in all 50 states: (1) VA Informatics and Computing Infrastructure (VINCI), with data from Veteran Health Administration's 151 inpatient and 909 ambulatory care and community-based outpatient clinics; (2) the University of California Research exchange (UC-ReX) network, with data from UC Davis, Irvine, Los Angeles, San Francisco, and San Diego; and (3) SCANNER, a consortium of UCSD, Tennessee VA, and three federally qualified health systems in the Los Angeles area supplemented with claims and health information exchange data, led by the University of Southern California. Initial use cases will focus on three conditions: (1) congestive heart failure; (2) Kawasaki disease; (3) obesity. Stakeholders, such as patients, clinicians, and health service researchers, will be engaged to prioritize research questions to be answered through the network. We will use a privacy-preserving distributed computation model with synchronous and asynchronous modes. The distributed system will be based on a common data model that allows the construction and evaluation of distributed multivariate models for a variety of statistical analyses. PMID:24780722

Pharmacogenetics of drug response in Parkinson's disease.

PubMed

Džoljić, Eleonora; Novaković, Ivana; Krajinovic, Maja; Grbatinić, Ivan; Kostić, Vladimir

2015-01-01

Parkinson's disease (PD) is a debilitating, demoralizing and financially devastating condition affecting 1% of population at the age of 60 years. Thus, very important issue to address is individual therapy optimization. Recent results have shown evidence that variable efficacy of treatment and risk of motor and mental complications could have genetic origin. Significant roles in that process play (pharmaco)genomic/genetic studies of PD. Variability in genes coding for drug-metabolizing enzymes, drug receptors and proteins involved in drug pathway signaling is an important factor determining inter-individual variability in drug responses. Interpersonal differences in drug responses are clearly documented although individualized treatment of PD is not widely known. Treatment with antiparkinsonian drugs is associated with the development of complications, such as L-DOPA-induced dyskinesia (LID), hallucinations and excessive daytime sleepiness. Carriers of specific genetic polymorphisms are particularly susceptible to development of some of these drug adverse effects. Pharmacogenomics aims to understand the relationship between genetic factors and inter-individual variations in drug responses, and to translate this information in therapy tailored to individual patient genetics. Relatively few efforts have been made to investigate the role of pharmacogenetics in the individual response to anti-PD drugs. Thus, many genetic variations and polymorphisms in myriad of different proteins can influence individual response to anti-PD drugs.

Integrated Network Testbed for Energy Grid Research and Technology

Science.gov Websites

Network Testbed for Energy Grid Research and Technology Experimentation Project Under the Integrated Network Testbed for Energy Grid Research and Technology Experimentation (INTEGRATE) project, NREL and partners completed five successful technology demonstrations at the ESIF. INTEGRATE is a $6.5-million, cost

Advancing Health Professions Education Research by Creating a Network of Networks.

PubMed

Carney, Patricia A; Brandt, Barbara; Dekhtyar, Michael; Holmboe, Eric S

2018-02-27

Producing the best evidence to show educational outcomes, such as competency achievement and credentialing effectiveness, across the health professions education continuum will require large multisite research projects and longitudinal studies. Current limitations that must be overcome to reach this goal include the prevalence of single-institution study designs, assessments of a single curricular component, and cross-sectional study designs that provide only a snapshot in time of a program or initiative rather than a longitudinal perspective.One solution to overcoming these limitations is to develop a network of networks that collaborates, using longitudinal approaches, across health professions and regions of the United States. Currently, individual networks are advancing educational innovation toward understanding the effectiveness of educational and credentialing programs. Examples of such networks include: (1) the American Medical Association's Accelerating Change in Medical Education initiative, (2) the National Center for Interprofessional Practice and Education, and (3) the Accreditation Council for Graduate Medical Education's Accreditation System. In this Invited Commentary, the authors briefly profile these existing networks, identify their progress and the challenges they have encountered, and propose a vigorous way forward toward creating a national network of networks designed to determine the effectiveness of health professions education and credentialing.

Research on scheme of applying ASON to current networks

NASA Astrophysics Data System (ADS)

Mao, Y. F.; Li, J. R.; Deng, L. J.

2008-10-01

Automatically Switched Optical Network (ASON) is currently a new and hot research subject in the world. It can provide high bandwidth, high assembly flexibility, high network security and reliability, but with a low management cost. It is presented to meet the requirements for high-throughput optical access with stringent Quality of Service (QoS). But as a brand new technology, ASON can not be supported by the traditional protocol software and network equipments. And the approach to build a new ASON network on the basis of completely abandoning the traditional optical network facilities is not desirable, because it costs too much and wastes a lot of network resources can also be used. So how to apply ASON to the current networks and realize the smooth transition between the existing network and ASON has been a serious problem to many network operators. In this research, the status in quo of ASON is introduced first and then the key problems should be considered when applying ASON to current networks are discussed. Based on this, the strategies should be complied with to overcome these key problems are listed. At last, the approach to apply ASON to the current optical networks is proposed and analyzed.

Donepezil in Alzheimer’s disease: From conventional trials to pharmacogenetics

PubMed Central

Cacabelos, Ramón

2007-01-01

(EM)(*1/*1, *1/*10) (57.47%) and intermediate metabolizers (IM)(*1/*3, *1/*5, *1/*6, *7/*10) (25.29%), and the worst responders are the poor (PM) (*4/*4)(9.20%) and ultra-rapid metabolizers (UM) (*1×N/*1) (8.04%). Pharmacogenetic and pharmacogenomic factors may account for 75%–85% of the therapeutic response in AD patients treated with donepezil and other AChEIs metabolized via enzymes of the CYP family. The implementation of pharmacogenetic protocols can optimize AD therapeutics. PMID:19300564

How Might Better Network Theories Support School Leadership Research?

ERIC Educational Resources Information Center

Hadfield, Mark; Jopling, Michael

2012-01-01

This article explores how recent research in education has applied different aspects of "network" theory to the study of school leadership. Constructs from different network theories are often used because of their perceived potential to clarify two perennial issues in leadership research. The first is the relative importance of formal and…

Pharmacogenetics of ustekinumab in patients with moderate-to-severe plaque psoriasis.

PubMed

Prieto-Pérez, Rocío; Llamas-Velasco, Mar; Cabaleiro, Teresa; Solano-López, Guillermo; Márquez, Beatriz; Román, Manuel; Ochoa, Dolores; Talegón, María; Daudén, Esteban; Abad-Santos, Francisco

2017-01-01

Aim/Materials & methods: Few studies have evaluated the influence of pharmacogenetics in psoriatic patients treated with ustekinumab. We evaluated 121 polymorphisms to study a possible association between these SNPs and the response to ustekinumab (PASI75 at 4 months; n = 69). The adjusted results (false discovery rate) showed an association between five SNPs in TNFRSF1A, HTR2A, NFKBIA, ADAM33 and IL13 genes, and poor response to ustekinumab. Furthermore, six SNPs in CHUK, C17orf51, ZNF816A, STAT4, SLC22A4 and Corf72 genes were associated with better response to ustekinumab. However, there was no significant association between response to ustekinumab and SNPs in HLA-C as it has been recently described. Finally, a higher weight was obtained in nonresponders than responders (p = 0.018). Further studies would be necessary to be closer to personalized medicine.

Facilitative Components of Collaborative Learning: A Review of Nine Health Research Networks.

PubMed

Leroy, Lisa; Rittner, Jessica Levin; Johnson, Karin E; Gerteis, Jessie; Miller, Therese

2017-02-01

Collaborative research networks are increasingly used as an effective mechanism for accelerating knowledge transfer into policy and practice. This paper explored the characteristics and collaborative learning approaches of nine health research networks. Semi-structured interviews with representatives from eight diverse US health services research networks conducted between November 2012 and January 2013 and program evaluation data from a ninth. The qualitative analysis assessed each network's purpose, duration, funding sources, governance structure, methods used to foster collaboration, and barriers and facilitators to collaborative learning. The authors reviewed detailed notes from the interviews to distill salient themes. Face-to-face meetings, intentional facilitation and communication, shared vision, trust among members and willingness to work together were key facilitators of collaborative learning. Competing priorities for members, limited funding and lack of long-term support and geographic dispersion were the main barriers to coordination and collaboration across research network members. The findings illustrate the importance of collaborative learning in research networks and the challenges to evaluating the success of research network functionality. Conducting readiness assessments and developing process and outcome evaluation metrics will advance the design and show the impact of collaborative research networks. Copyright © 2017 Longwoods Publishing.

Dengue research networks: building evidence for policy and planning in Brazil.

PubMed

de Paula Fonseca E Fonseca, Bruna; Zicker, Fabio

2016-11-08

The analysis of scientific networks has been applied in health research to map and measure relationships between researchers and institutions, describing collaboration structures, individual roles, and research outputs, and helping the identification of knowledge gaps and cooperation opportunities. Driven by dengue continued expansion in Brazil, we explore the contribution, dynamics and consolidation of dengue scientific networks that could ultimately inform the prioritisation of research, financial investments and health policy. Social network analysis (SNA) was used to produce a 20-year (1995-2014) retrospective longitudinal evaluation of dengue research networks within Brazil and with its partners abroad, with special interest in describing institutional collaboration and their research outputs. The analysis of institutional co-authorship showed a significant expansion of collaboration over the years, increased international involvement, and ensured a shift from public health research toward vector control and basic biomedical research, probably as a reflection of the expansion of transmission, high burden and increasing research funds from the Brazilian government. The analysis identified leading national organisations that maintained the research network connectivity, facilitated knowledge exchange and reduced network vulnerability. SNA proved to be a valuable tool that, along with other indicators, can strengthen a knowledge platform to inform future policy, planning and funding decisions. The paper provides relevant information to policy and planning for dengue research as it reveals: (1) the effectiveness of the research network in knowledge generation, sharing and diffusion; (2) the near-absence of collaboration with the private sector; and (3) the key central organisations that can support strategic decisions on investments, development and implementation of innovations. In addition, the increase in research activities and collaboration has not yet

Role of pharmacogenetics in public health and clinical health care: a SWOT analysis

PubMed Central

Kapoor, Ritika; Tan-Koi, Wei Chuen; Teo, Yik-Ying

2016-01-01

Pharmacogenomics has been lauded as an important innovation in clinical medicine as a result of advances in genomic science. As one of the cornerstones in precision medicine, the vision to determine the right medication in the right dosage for the right treatment with the use of genetic information has not exactly materialised, and few genetic tests have been implemented as the standard of care in health systems worldwide. Here we review the findings from a SWOT analysis to examine the strengths, weaknesses, opportunities and threats around the role of pharmacogenetics in public health and clinical health care, at the micro, meso and macro levels corresponding to the perspectives of the individuals (scientists, patients and physicians), the health-care institutions and the health systems, respectively. PMID:27577547

Role of pharmacogenetics in public health and clinical health care: a SWOT analysis.

PubMed

Kapoor, Ritika; Tan-Koi, Wei Chuen; Teo, Yik-Ying

2016-12-01

Pharmacogenomics has been lauded as an important innovation in clinical medicine as a result of advances in genomic science. As one of the cornerstones in precision medicine, the vision to determine the right medication in the right dosage for the right treatment with the use of genetic information has not exactly materialised, and few genetic tests have been implemented as the standard of care in health systems worldwide. Here we review the findings from a SWOT analysis to examine the strengths, weaknesses, opportunities and threats around the role of pharmacogenetics in public health and clinical health care, at the micro, meso and macro levels corresponding to the perspectives of the individuals (scientists, patients and physicians), the health-care institutions and the health systems, respectively.

Vehicular-networking- and road-weather-related research in Sodankylä

NASA Astrophysics Data System (ADS)

Sukuvaara, Timo; Mäenpää, Kari; Ylitalo, Riika

2016-10-01

Vehicular-networking- and especially safety-related wireless vehicular services have been under intensive research for almost a decade now. Only in recent years has road weather information also been acknowledged to play an important role when aiming to reduce traffic accidents and fatalities via intelligent transport systems (ITSs). Part of the progress can be seen as a result of the Finnish Meteorological Institute's (FMI) long-term research work in Sodankylä within the topic, originally started in 2006. Within multiple research projects, the FMI Arctic Research Centre has been developing wireless vehicular networking and road weather services, in co-operation with the FMI meteorological services team in Helsinki. At the beginning the wireless communication was conducted with traditional Wi-Fi type local area networking, but during the development the system has evolved into a hybrid communication system of a combined vehicular ad hoc networking (VANET) system with special IEEE 802.11p protocol and supporting cellular networking based on a commercial 3G network, not forgetting support for Wi-Fi-based devices also. For piloting purposes and further research, we have established a special combined road weather station (RWS) and roadside unit (RSU), to interact with vehicles as a service hotspot. In the RWS-RSU we have chosen to build support to all major approaches, IEEE 802.11, traditional Wi-Fi and cellular 3G. We employ road weather systems of FMI, along with RWS and vehicle data gathered from vehicles, in the up-to-date localized weather data delivered in real time. IEEE 802.11p vehicular networking is supported with Wi-Fi and 3G communications. This paper briefly introduces the research work related to vehicular networking and road weather services conducted in Sodankylä, as well as the research project involved in this work. The current status of instrumentation, available services and capabilities are presented in order to formulate a clear general view of

Exploring Knowledge Processes Based on Teacher Research in a School-University Research Network of a Master's Program

ERIC Educational Resources Information Center

Cornelissen, Frank; van Swet, Jacqueline; Beijaard, Douwe; Bergen, Theo

2013-01-01

School-university research networks aim at closer integration of research and practice by means of teacher research. Such practice-oriented research can benefit both schools and universities. This paper reports on a multiple-case study of five participants in a school-university research network in a Dutch master's program. The research question…

Analysing published global Ebola Virus Disease research using social network analysis.

PubMed

Hagel, Christiane; Weidemann, Felix; Gauch, Stephan; Edwards, Suzanne; Tinnemann, Peter

2017-10-01

The 2014/2015 West African Ebola Virus Disease (EVD) outbreak attracted global attention. Numerous opinions claimed that the global response was impaired, in part because, the EVD research was neglected, although quantitative or qualitative studies did not exist. Our objective was to analyse how the EVD research landscape evolved by exploring the existing research network and its communities before and during the outbreak in West Africa. Social network analysis (SNA) was used to analyse collaborations between institutions named by co-authors as affiliations in publications on EVD. Bibliometric data of publications on EVD between 1976 and 2015 was collected from Thomson Reuters' Web of Science Core Collection (WoS). Freely available software was used for network analysis at a global-level and for 10-year periods. The networks are presented as undirected-weighted graphs. Rankings by degree and betweenness were calculated to identify central and powerful network positions; modularity function was used to identify research communities. Overall 4,587 publications were identified, of which 2,528 were original research articles. Those yielded 1,644 authors' affiliated institutions and 9,907 connections for co-authorship network construction. The majority of institutions were from the USA, Canada and Europe. Collaborations with research partners on the African continent did exist, but less frequently. Around six highly connected organisations in the network were identified with powerful and broker positions. Network characteristics varied widely among the 10-year periods and evolved from 30 to 1,489 institutions and 60 to 9,176 connections respectively. Most influential actors are from public or governmental institutions whereas private sector actors, in particular the pharmaceutical industry, are largely absent. Research output on EVD has increased over time and surged during the 2014/2015 outbreak. The overall EVD research network is organised around a few key actors

The use and significance of a research networking system.

PubMed

Kahlon, Maninder; Yuan, Leslie; Daigre, John; Meeks, Eric; Nelson, Katie; Piontkowski, Cynthia; Reuter, Katja; Sak, Rachael; Turner, Brian; Weber, Griffin M; Chatterjee, Anirvan

2014-02-07

Universities have begun deploying public Internet systems that allow for easy search of their experts, expertise, and intellectual networks. Deployed first in biomedical schools but now being implemented more broadly, the initial motivator of these research networking systems was to enable easier identification of collaborators and enable the development of teams for research. The intent of the study was to provide the first description of the usage of an institutional research "social networking" system or research networking system (RNS). Number of visits, visitor location and type, referral source, depth of visit, search terms, and click paths were derived from 2.5 years of Web analytics data. Feedback from a pop-up survey presented to users over 15 months was summarized. RNSs automatically generate and display profiles and networks of researchers. Within 2.5 years, the RNS at the University of California, San Francisco (UCSF) achieved one-seventh of the monthly visit rate of the main longstanding university website, with an increasing trend. Visitors came from diverse locations beyond the institution. Close to 75% (74.78%, 208,304/278,570) came via a public search engine and 84.0% (210 out of a sample of 250) of these queried an individual's name that took them directly to the relevant profile page. In addition, 20.90% (214 of 1024) visits went beyond the page related to a person of interest to explore related researchers and topics through the novel and networked information provided by the tool. At the end of the period analyzed, more than 2000 visits per month traversed 5 or more links into related people and topics. One-third of visits came from returning visitors who were significantly more likely to continue to explore networked people and topics (P<.001). Responses to an online survey suggest a broad range of benefits of using the RNS in supporting the research and clinical mission. Returning visitors in an ever-increasing pool of visitors to an RNS are

ALEPH: Israel's Research Library Network: Background, Evolution, and Implications for Networking in a Small Country.

ERIC Educational Resources Information Center

Lazinger, Susan S.

1991-01-01

Describes ALEPH, the research library network in Israel, and analyzes the strengths and weaknesses of its decentralized structure. Highlights include comparisons between RLIN and ALEPH; centralized versus decentralized networks; the format of ALEPH; authority control in ALEPH; and non-Roman scripts in both networks. (16 references) (LRW)

A Federated Network for Translational Cancer Research Using Clinical Data and Biospecimens

PubMed Central

Becich, Michael J.; Bollag, Roni J.; Chavan, Girish; Corrigan, Julia; Dhir, Rajiv; Feldman, Michael D.; Gaudioso, Carmelo; Legowski, Elizabeth; Maihle, Nita J.; Mitchell, Kevin; Murphy, Monica; Sakthivel, Mayur; Tseytlin, Eugene; Weaver, JoEllen

2015-01-01

Advances in cancer research and personalized medicine will require significant new bridging infrastructures, including more robust biorepositories that link human tissue to clinical phenotypes and outcomes. In order to meet that challenge, four cancer centers formed the TIES Cancer Research Network, a federated network that facilitates data and biospecimen sharing among member institutions. Member sites can access pathology data that is de-identified and processed with the TIES natural language processing system, which creates a repository of rich phenotype data linked to clinical biospecimens. TIES incorporates multiple security and privacy best practices that, combined with legal agreements, network policies and procedures, enable regulatory compliance. The TIES Cancer Research Network now provides integrated access to investigators at all member institutions, where multiple investigator-driven pilot projects are underway. Examples of federated search across the network illustrate the potential impact on translational research, particularly for studies involving rare cancers, rare phenotypes, and specific biologic behaviors. The network satisfies several key desiderata including local control of data and credentialing, inclusion of rich phenotype information, and applicability to diverse research objectives. The TIES Cancer Research Network presents a model for a national data and biospecimen network. PMID:26670560

Facilitative Components of Collaborative Learning: A Review of Nine Health Research Networks

PubMed Central

Rittner, Jessica Levin; Johnson, Karin E.; Gerteis, Jessie; Miller, Therese

2017-01-01

Objective: Collaborative research networks are increasingly used as an effective mechanism for accelerating knowledge transfer into policy and practice. This paper explored the characteristics and collaborative learning approaches of nine health research networks. Data sources/study setting: Semi-structured interviews with representatives from eight diverse US health services research networks conducted between November 2012 and January 2013 and program evaluation data from a ninth. Study design: The qualitative analysis assessed each network's purpose, duration, funding sources, governance structure, methods used to foster collaboration, and barriers and facilitators to collaborative learning. Data collection: The authors reviewed detailed notes from the interviews to distill salient themes. Principal findings: Face-to-face meetings, intentional facilitation and communication, shared vision, trust among members and willingness to work together were key facilitators of collaborative learning. Competing priorities for members, limited funding and lack of long-term support and geographic dispersion were the main barriers to coordination and collaboration across research network members. Conclusion: The findings illustrate the importance of collaborative learning in research networks and the challenges to evaluating the success of research network functionality. Conducting readiness assessments and developing process and outcome evaluation metrics will advance the design and show the impact of collaborative research networks. PMID:28277202

National research and education network

NASA Technical Reports Server (NTRS)

Villasenor, Tony

1991-01-01

Some goals of this network are as follows: Extend U.S. technological leadership in high performance computing and computer communications; Provide wide dissemination and application of the technologies both to the speed and the pace of innovation and to serve the national economy, national security, education, and the global environment; and Spur gains in the U.S. productivity and industrial competitiveness by making high performance computing and networking technologies an integral part of the design and production process. Strategies for achieving these goals are as follows: Support solutions to important scientific and technical challenges through a vigorous R and D effort; Reduce the uncertainties to industry for R and D and use of this technology through increased cooperation between government, industry, and universities and by the continued use of government and government funded facilities as a prototype user for early commercial HPCC products; and Support underlying research, network, and computational infrastructures on which U.S. high performance computing technology is based.

Leadership in complex networks: the importance of network position and strategic action in a translational cancer research network.

PubMed

Long, Janet C; Cunningham, Frances C; Wiley, Janice; Carswell, Peter; Braithwaite, Jeffrey

2013-10-11

Leadership behaviour in complex networks is under-researched, and little has been written concerning leadership of translational research networks (TRNs) that take discoveries made 'at the bench' and translate them into practices used 'at the bedside.' Understanding leaders' opportunities and behaviours within TRNs working to solve this key problem in implementing evidence into clinical practice is therefore important. This study explored the network position of governing body members and perceptions of their role in a new TRN in Sydney, Australia. The paper asks three questions: Firstly, do the formal, mandated leaders of this TRN hold key positions of centrality or brokerage in the informal social network of collaborative ties? Secondly, if so, do they recognise the leadership opportunities that their network positions afford them? Thirdly, what activities associated with these key roles do they believe will maximise the TRN's success? Semi-structured interviews of all 14 governing body members conducted in early 2012 explored perceptions of their roles and sought comments on a list of activities drawn from review of successful transdisciplinary collaboratives combined with central and brokerage roles. An on-line, whole network survey of all 68 TRN members sought to understand and map existing collaborative connections. Leaders' positions in the network were assessed using UCInet, and graphs were generated in NetDraw. Social network analysis identified that governing body members had high centrality and high brokerage potential in the informal network of work-related ties. Interviews showed perceived challenges including 'silos' and the mismatch between academic and clinical goals of research. Governing body members recognised their central positions, which would facilitate the leadership roles of leading, making decisions, and providing expert advice necessary for the co-ordination of effort and relevant input across domains. Brokerage potential was recognised

Leadership in complex networks: the importance of network position and strategic action in a translational cancer research network

PubMed Central

2013-01-01

Background Leadership behaviour in complex networks is under-researched, and little has been written concerning leadership of translational research networks (TRNs) that take discoveries made ‘at the bench’ and translate them into practices used ‘at the bedside.’ Understanding leaders’ opportunities and behaviours within TRNs working to solve this key problem in implementing evidence into clinical practice is therefore important. This study explored the network position of governing body members and perceptions of their role in a new TRN in Sydney, Australia. The paper asks three questions: Firstly, do the formal, mandated leaders of this TRN hold key positions of centrality or brokerage in the informal social network of collaborative ties? Secondly, if so, do they recognise the leadership opportunities that their network positions afford them? Thirdly, what activities associated with these key roles do they believe will maximise the TRN’s success? Methods Semi-structured interviews of all 14 governing body members conducted in early 2012 explored perceptions of their roles and sought comments on a list of activities drawn from review of successful transdisciplinary collaboratives combined with central and brokerage roles. An on-line, whole network survey of all 68 TRN members sought to understand and map existing collaborative connections. Leaders’ positions in the network were assessed using UCInet, and graphs were generated in NetDraw. Results Social network analysis identified that governing body members had high centrality and high brokerage potential in the informal network of work-related ties. Interviews showed perceived challenges including ‘silos’ and the mismatch between academic and clinical goals of research. Governing body members recognised their central positions, which would facilitate the leadership roles of leading, making decisions, and providing expert advice necessary for the co-ordination of effort and relevant input across

Research on centrality of urban transport network nodes

NASA Astrophysics Data System (ADS)

Wang, Kui; Fu, Xiufen

2017-05-01

Based on the actual data of urban transport in Guangzhou, 19,150 bus stations in Guangzhou (as of 2014) are selected as nodes. Based on the theory of complex network, the network model of Guangzhou urban transport is constructed. By analyzing the degree centrality index, betweenness centrality index and closeness centrality index of nodes in the network, the level of centrality of each node in the network is studied. From a different point of view to determine the hub node of Guangzhou urban transport network, corresponding to the city's key sites and major transfer sites. The reliability of the network is determined by the stability of some key nodes (transport hub station). The research of network node centralization can provide a theoretical basis for the rational allocation of urban transport network sites and public transport system planning.

European Network of Bipolar Research Expert Centre (ENBREC): a network to foster research and promote innovative care.

PubMed

Henry, Chantal; Andreassen, Ole A; Barbato, Angelo; Demotes-Mainard, Jacques; Goodwin, Guy; Leboyer, Marion; Vieta, Eduard; Nolen, Willem A; Kessing, Lars Vedel; Scott, Jan; Bauer, Michael

2013-01-01

Bipolar disorders rank as one of the most disabling illnesses in working age adults worldwide. Despite this, the quality of care offered to patients with this disorder is suboptimal, largely due to limitations in our understanding of the pathology. Improving this scenario requires the development of a critical mass of expertise and multicentre collaborative projects. Within the framework of the European FP7 programme, we developed a European Network of Bipolar Research Expert Centres (ENBREC) designed specifically to facilitate EU-wide studies. ENBREC provides an integrated support structure facilitating research on disease mechanisms and clinical outcomes across six European countries (France, Germany, Italy, Norway, Spain and the UK). The centres are adopting a standardised clinical assessment that explores multiple aspects of bipolar disorder through a structured evaluation designed to inform clinical decision-making as well as being applicable to research. Reliable, established measures have been prioritised, and instruments have been translated and validated when necessary. An electronic healthcare record and monitoring system (e-ENBREC©) has been developed to collate the data. Protocols to conduct multicentre clinical observational studies and joint studies on cognitive function, biomarkers, genetics, and neuroimaging are in progress; a pilot study has been completed on strategies for routine implementation of psycho-education. The network demonstrates 'proof of principle' that expert centres across Europe can collaborate on a wide range of basic science and clinical programmes using shared protocols. This paper is to describe the network and how it aims to improve the quality and effectiveness of research in a neglected priority area.

Online social networks for patient involvement and recruitment in clinical research.

PubMed

Ryan, Gemma Sinead

2013-01-01

To review current literature and discuss the potential of online social networking to engage patients and the public and recruit and retain participants in clinical research. Online social networking is becoming a large influence on people's daily lives. Clinical research faces several challenges, with an increasing need to engage with patients and the public and for studies to recruit and retain increasing numbers of participants, particularly in under-served, under-represented and hard to reach groups and communities. Searches were conducted using EMBASE, BNI, ERIC, CINAHL, PSYCHinfo online databases and Google Scholar to identify any grey or unpublished literature that may be available. Review methods This is a methodology paper. Online social networking is a successful, cost-effective and efficient method by which to target and recruit a wide range of communities, adolescents, young people and underserved populations into quantitative and qualitative research. Retention of participants in longitudinal studies could be improved using social networks such as Facebook. Evidence indicates that a mixed approach to recruitment using social networking and traditional methods is most effective. Further research is required to strengthen the evidence available, especially in dissemination of research through online social networks. Researchers should consider using online social networking as a method of engaging the public, and also for the recruitment and follow up of participants.

Contrast research of CDMA and GSM network optimization

NASA Astrophysics Data System (ADS)

Wu, Yanwen; Liu, Zehong; Zhou, Guangyue

2004-03-01

With the development of mobile telecommunication network, users of CDMA advanced their request of network service quality. While the operators also change their network management object from signal coverage to performance improvement. In that case, reasonably layout & optimization of mobile telecommunication network, reasonably configuration of network resource, improvement of the service quality, and increase the enterprise's core competition ability, all those have been concerned by the operator companies. This paper firstly looked into the flow of CDMA network optimization. Then it dissertated to some keystones in the CDMA network optimization, like PN code assignment, calculation of soft handover, etc. As GSM is also the similar cellular mobile telecommunication system like CDMA, so this paper also made a contrast research of CDMA and GSM network optimization in details, including the similarity and the different. In conclusion, network optimization is a long time job; it will run through the whole process of network construct. By the adjustment of network hardware (like BTS equipments, RF systems, etc.) and network software (like parameter optimized, configuration optimized, capacity optimized, etc.), network optimization work can improve the performance and service quality of the network.

NC truck network model development research.

DOT National Transportation Integrated Search

2008-09-01

This research develops a validated prototype truck traffic network model for North Carolina. The model : includes all counties and metropolitan areas of North Carolina and major economic areas throughout the : U.S. Geographic boundaries, population a...

Pharmacogenetics and breast cancer management: current status and perspectives.

PubMed

Ciccolini, Joseph; Fanciullino, Raphaelle; Serdjebi, Cindy; Milano, Gérard

2015-05-01

Breast cancer has benefited from a number of innovative therapeutics over the last decade. Cytotoxics, hormone therapy, targeted therapies and biologics can now be given to ensure optimal management of patients. As life expectancy of breast cancer patients has been significantly stretched and that several lines of treatment are now made available, determining the best drug or drug combinations to be primarily given and the best dosing and scheduling for each patient is critical for ensuring an optimal toxicity/efficacy balance. Defining patient's characteristics at the tumor level (pharmacogenomics) and the constitutional level (pharmacogenetics) is a rising trend in oncology. This review covers the latest strategies based upon the search of relevant biomarkers for efficacy, resistance and toxicity to be undertaken at the bedside to shift towards precision medicine in breast cancer patients. In the expanding era of bioguided medicine, identifying relevant and clinically validated biomarkers from the plethora of published material remains an uneasy task. Sorting the variety of genetic and molecular markers that have been investigated over the last decade on their level of evidence and addressing the issue of drug exposure should help to improve the management of breast cancer therapy.

A Space Operations Network Alternative: Using Globally Connected Research and Education Networks for Space-Based Science Operations

NASA Technical Reports Server (NTRS)

Bradford, Robert N.

2006-01-01

Earth based networking in support of various space agency projects has been based on leased service/circuits which has a high associated cost. This cost is almost always taken from the science side resulting in less science. This is a proposal to use Research and Education Networks (RENs) worldwide to support space flight operations in general and space-based science operations in particular. The RENs were developed to support scientific and educational endeavors. They do not provide support for general Internet traffic. The connectivity and performance of the research and education networks is superb. The connectivity at Layer 3 (IP) virtually encompasses the globe. Most third world countries and all developed countries have their own research and education networks, which are connected globally. Performance of the RENs especially in the developed countries is exceptional. Bandwidth capacity currently exists and future expansion promises that this capacity will continue. REN performance statistics has always exceeded minimum requirements for spaceflight support. Research and Education networks are more loosely managed than a corporate network but are highly managed when compared to the commodity Internet. Management of RENs on an international level is accomplished by the International Network Operations Center at Indiana University at Indianapolis. With few exceptions, each regional and national REN has its own network ops center. The acceptable use policies (AUP), although differing by country, allows any scientific program or project the use of their networks. Once in compliance with the first RENs AUP, all others will accept that specific traffic including regional and transoceanic networks. RENs can support spaceflight related scientific programs and projects. Getting the science to the researcher is obviously key to any scientific project. RENs provide a pathway to virtually any college or university in the world, as well as many governmental institutes and

Building a Community of Practice for Researchers: The International Network for Simulation-Based Pediatric Innovation, Research and Education.

PubMed

Cheng, Adam; Auerbach, Marc; Calhoun, Aaron; Mackinnon, Ralph; Chang, Todd P; Nadkarni, Vinay; Hunt, Elizabeth A; Duval-Arnould, Jordan; Peiris, Nicola; Kessler, David

2018-06-01

The scope and breadth of simulation-based research is growing rapidly; however, few mechanisms exist for conducting multicenter, collaborative research. Failure to foster collaborative research efforts is a critical gap that lies in the path of advancing healthcare simulation. The 2017 Research Summit hosted by the Society for Simulation in Healthcare highlighted how simulation-based research networks can produce studies that positively impact the delivery of healthcare. In 2011, the International Network for Simulation-based Pediatric Innovation, Research and Education (INSPIRE) was formed to facilitate multicenter, collaborative simulation-based research with the aim of developing a community of practice for simulation researchers. Since its formation, the network has successfully completed and published numerous collaborative research projects. In this article, we describe INSPIRE's history, structure, and internal processes with the goal of highlighting the community of practice model for other groups seeking to form a simulation-based research network.

Molecular Targets in Advanced Therapeutics of Cancers: The Role of Pharmacogenetics.

PubMed

Abubakar, Murtala B; Gan, Siew Hua

2016-01-01

The advent of advanced molecular targeted therapy has resulted in improved prognoses for patients with advanced malignancies. However, despite the significant success and specificity of this advocated targeted therapy, significant on- and off-target adverse effects and inter-individual variability in treatment responses have been reported. The interpatient variability in drug response has been suggested to be partly due to variations in patient genomes. Therefore, the identification of genetic biomarkers by conducting pharmacogenetics studies can help predict patient responses to targeted therapy and may serve as a basis for individualized treatment. In this review, both clinically established and potential molecular targets are highlighted. Overall, current literature suggests that individualization of targeted therapy is promising; however, integrating the clinical benefits of identified biomarkers into clinical practice for personalized medicine remains a major challenge, and further studies to validate these markers and identify novel therapeutic approaches are needed. © 2016 S. Karger AG, Basel.

Subjective response as a consideration in the pharmacogenetics of alcoholism treatment.

PubMed

Roche, Daniel Jo; Ray, Lara A

2015-01-01

Currently available pharmacological treatments for alcoholism have modest efficacy and high individual variability in treatment outcomes, both of which have been partially attributed to genetic factors. One path to reducing the variability and improving the efficacy associated with these pharmacotherapies may be to identify overlapping genetic contributions to individual differences in both subjective responses to alcohol and alcoholism pharmacotherapy outcomes. As acute subjective response to alcohol is highly predictive of future alcohol related problems, identifying such shared genetic mechanisms may inform the development of personalized treatments that can effectively target converging pathophysiological mechanisms that convey risk for alcoholism. The focus of this review is to revisit the association between subjective response to alcohol and the etiology of alcoholism while also describing genetic contributions to this relationship, discuss potential pharmacogenetic approaches to target subjective response to alcohol in order to improve the treatment of alcoholism and examine conceptual and methodological issues associated with these topics, and outline future approaches to overcome these challenges.

Pilot study: incorporation of pharmacogenetic testing in medication therapy management services.

PubMed

Haga, Susanne B; Allen LaPointe, Nancy M; Moaddeb, Jivan; Mills, Rachel; Patel, Mahesh; Kraus, William E

2014-11-01

Aim: To describe the rationale and design of a pilot study evaluating the integration of pharmacogenetic (PGx) testing into pharmacist-delivered medication therapy management (MTM). Study rationale: Clinical delivery approaches of PGx testing involving pharmacists may overcome barriers of limited physician knowledge about and experience with testing. Study design: We will assess the addition of PGx testing to MTM services for cardiology patients taking three or more medications including simvastatin or clopidogrel. We will measure the impact of MTM plus PGx testing on drug/dose adjustment and clinical outcomes. Factors associated with delivery, such as time to prepare and conduct MTM and consult with physicians will be recorded. Additionally, patient interest and satisfaction will be measured. Anticipated results: We anticipate that PGx testing can be practically integrated into standard a MTM service, providing a viable delivery model for testing. Conclusion: Given the lack of evidence of an effective PGx delivery models, this study will provide preliminary evidence regarding a pharmacist-delivered approach.

Structure and Evolution of Scientific Collaboration Networks in a Modern Research Collaboratory

ERIC Educational Resources Information Center

Pepe, Alberto

2010-01-01

This dissertation is a study of scientific collaboration at the Center for Embedded Networked Sensing (CENS), a modern, multi-disciplinary, distributed laboratory involved in sensor network research. By use of survey research and network analysis, this dissertation examines the collaborative ecology of CENS in terms of three networks of…

Analysing published global Ebola Virus Disease research using social network analysis

PubMed Central

Hagel, Christiane; Weidemann, Felix; Gauch, Stephan; Edwards, Suzanne

2017-01-01

Introduction The 2014/2015 West African Ebola Virus Disease (EVD) outbreak attracted global attention. Numerous opinions claimed that the global response was impaired, in part because, the EVD research was neglected, although quantitative or qualitative studies did not exist. Our objective was to analyse how the EVD research landscape evolved by exploring the existing research network and its communities before and during the outbreak in West Africa. Methods/ Principal findings Social network analysis (SNA) was used to analyse collaborations between institutions named by co-authors as affiliations in publications on EVD. Bibliometric data of publications on EVD between 1976 and 2015 was collected from Thomson Reuters’ Web of Science Core Collection (WoS). Freely available software was used for network analysis at a global-level and for 10-year periods. The networks are presented as undirected-weighted graphs. Rankings by degree and betweenness were calculated to identify central and powerful network positions; modularity function was used to identify research communities. Overall 4,587 publications were identified, of which 2,528 were original research articles. Those yielded 1,644 authors’ affiliated institutions and 9,907 connections for co-authorship network construction. The majority of institutions were from the USA, Canada and Europe. Collaborations with research partners on the African continent did exist, but less frequently. Around six highly connected organisations in the network were identified with powerful and broker positions. Network characteristics varied widely among the 10-year periods and evolved from 30 to 1,489 institutions and 60 to 9,176 connections respectively. Most influential actors are from public or governmental institutions whereas private sector actors, in particular the pharmaceutical industry, are largely absent. Conclusion/ Significance Research output on EVD has increased over time and surged during the 2014/2015 outbreak. The

Practice-based Research Network Research Good Practices (PRGPs): Summary of Recommendations.

PubMed

Dolor, Rowena J; Campbell-Voytal, Kimberly; Daly, Jeanette; Nagykaldi, Zsolt J; O'Beirne, Maeve; Sterling, Pamela; Fagnan, Lyle J; Levy, Barcey; Michaels, LeAnn; Louks, Hannah A; Smith, Paul; Aspy, Cheryl B; Patterson, V Beth; Kano, Miria; Sussman, Andrew L; Williams, Robert; Neale, Anne Victoria

2015-12-01

Practice-based research networks (PBRNs) conduct research in community settings, which poses quality control challenges to the integrity of research, such as study implementation and data collection. A foundation for improving research processes within PBRNs is needed to ensure research integrity. Network directors and coordinators from seven U.S.-based PBRNs worked with a professional team facilitator during semiannual in-person meetings and monthly conference calls to produce content for a compendium of recommended research practices specific to the context of PBRNs. Participants were assigned to contribute content congruent with their expertise. Feedback on the draft document was obtained from attendees at the preconference workshop at the annual PBRN meeting in 2013. A revised document was circulated to additional PBRN peers prior to finalization. The PBRN Research Good Practices (PRGPs) document is organized into four chapters: (1) Building PBRN Infrastructure; (2) Study Development and Implementation; (3) Data Management, and (4) Dissemination Policies. Each chapter contains an introduction, detailed procedures for each section, and example resources with information links. The PRGPs is a PBRN-specific resource to facilitate PBRN management and staff training, to promote adherence to study protocols, and to increase validity and generalizability of study findings. © 2015 Wiley Periodicals, Inc.

Practice‐based Research Network Research Good Practices (PRGPs): Summary of Recommendations

PubMed Central

Campbell‐Voytal, Kimberly; Daly, Jeanette; Nagykaldi, Zsolt J.; O'Beirne, Maeve; Sterling, Pamela; Fagnan, Lyle J.; Levy, Barcey; Michaels, LeAnn; Louks, Hannah A.; Smith, Paul; Aspy, Cheryl B.; Patterson, V. Beth; Kano, Miria; Sussman, Andrew L.; Williams, Robert; Neale, Anne Victoria

2015-01-01

Abstract Introduction Practice‐based research networks (PBRNs) conduct research in community settings, which poses quality control challenges to the integrity of research, such as study implementation and data collection. A foundation for improving research processes within PBRNs is needed to ensure research integrity. Methods Network directors and coordinators from seven U.S.‐based PBRNs worked with a professional team facilitator during semiannual in‐person meetings and monthly conference calls to produce content for a compendium of recommended research practices specific to the context of PBRNs. Participants were assigned to contribute content congruent with their expertise. Feedback on the draft document was obtained from attendees at the preconference workshop at the annual PBRN meeting in 2013. A revised document was circulated to additional PBRN peers prior to finalization. Results The PBRN Research Good Practices (PRGPs) document is organized into four chapters: (1) Building PBRN Infrastructure; (2) Study Development and Implementation; (3) Data Management, and (4) Dissemination Policies. Each chapter contains an introduction, detailed procedures for each section, and example resources with information links. Conclusion The PRGPs is a PBRN‐specific resource to facilitate PBRN management and staff training, to promote adherence to study protocols, and to increase validity and generalizability of study findings. PMID:26296309

EEG-based research on brain functional networks in cognition.

PubMed

Wang, Niannian; Zhang, Li; Liu, Guozhong

2015-01-01

Recently, exploring the cognitive functions of the brain by establishing a network model to understand the working mechanism of the brain has become a popular research topic in the field of neuroscience. In this study, electroencephalography (EEG) was used to collect data from subjects given four different mathematical cognitive tasks: recite numbers clockwise and counter-clockwise, and letters clockwise and counter-clockwise to build a complex brain function network (BFN). By studying the connectivity features and parameters of those brain functional networks, it was found that the average clustering coefficient is much larger than its corresponding random network and the average shortest path length is similar to the corresponding random networks, which clearly shows the characteristics of the small-world network. The brain regions stimulated during the experiment are consistent with traditional cognitive science regarding learning, memory, comprehension, and other rational judgment results. The new method of complex networking involves studying the mathematical cognitive process of reciting, providing an effective research foundation for exploring the relationship between brain cognition and human learning skills and memory. This could help detect memory deficits early in young and mentally handicapped children, and help scientists understand the causes of cognitive brain disorders.

Impact of the Cancer Prevention and Control Research Network

PubMed Central

Ribisl, Kurt M.; Fernandez, Maria E.; Friedman, Daniela B.; Hannon, Peggy; Leeman, Jennifer; Moore, Alexis; Olson, Lindsay; Ory, Marcia; Risendal, Betsy; Sheble, Laura; Taylor, Vicky; Williams, Rebecca; Weiner, Bryan J.

2018-01-01

The Cancer Prevention and Control Research Network (CPCRN) is a thematic network dedicated to accelerating the adoption of evidence-based cancer prevention and control practices in communities by advancing dissemination and implementation science. Funded by the Centers for Disease Control and Prevention and National Cancer Institute, CPCRN has operated at two levels: Each participating Network Center conducts research projects with primarily local partners as well as multicenter collaborative research projects with state and national partners. Through multicenter collaboration, thematic networks leverage the expertise, resources, and partnerships of participating centers to conduct research projects collectively that might not be feasible individually. Although multicenter collaboration often is advocated, it is challenging to promote and assess. Using bibliometric network analysis and other graphical methods, this paper describes CPCRN’s multicenter publication progression from 2004 to 2014. Searching PubMed, Scopus, and Web of Science in 2014 identified 249 peer-reviewed CPCRN publications involving two or more centers out of 6,534 total. The research and public health impact of these multicenter collaborative projects initiated by CPCRN during that 10-year period were then examined. CPCRN established numerous workgroups around topics such as: 2-1-1, training and technical assistance, colorectal cancer control, federally qualified health centers, cancer survivorship, and human papillomavirus. The paper discusses the challenges that arise in promoting multicenter collaboration and the strategies that CPCRN uses to address those challenges. The lessons learned should broadly interest those seeking to promote multisite collaboration to address public health problems, such as cancer prevention and control. PMID:28215371

Technical research aspect of the Pan-Pacific Information Network using satellite

NASA Astrophysics Data System (ADS)

Iida, Takashi; Morikawa, Hisashi; Noguchi, Shoichi

The Pan-Pacific Information Network would provide an important new mechanism for education, research, health service, emergency communication, and cultural exchange. The paper discusses the technical research items related to the Pan-Pacific Information Network, reviews small earth-station systems, and considers the system configuration pointed to the network in the Asia/Pacific region.

Analyzing Online Teacher Networks: Cyber Networks Require Cyber Research Tools

ERIC Educational Resources Information Center

Schlager, Mark S.; Farooq, Umer; Fusco, Judith; Schank, Patricia; Dwyer, Nathan

2009-01-01

The authors argue that conceptual and methodological limitations in existing research approaches severely hamper theory building and empirical exploration of teacher learning and collaboration through cyber-enabled networks. They conclude that new frameworks, tools, and techniques are needed to understand and maximize the benefits of teacher…

Learning Networks--Enabling Change through Community Action Research

ERIC Educational Resources Information Center

Bleach, Josephine

2016-01-01

Learning networks are a critical element of ethos of the community action research approach taken by the Early Learning Initiative at the National College of Ireland, a community-based educational initiative in the Dublin Docklands. Key criteria for networking, whether at local, national or international level, are the individual's and…

Clinical aspects of pharmacogenetics of pain and co-morbidities of emotional distress.

PubMed

Kamen, Barton A

2010-01-01

The majority of patients treated for cancer will have pain at some point in their journey. It will be due to the disease (e.g. bone metastasis, fracture, organ invasion) or from iatrogenic causes (chemotherapy, surgery or radiation). A large number of patients will also have depression. Since pain and depression share common biological pathways and even neuro-transmitters it is not surprising that a comorbidity of pain is depression. It has already been reported that patients in severe pain are 4 times less likely to respond to therapy for depression. In recent years, especially in the era of molecular biology and post-genomic a wealth of data in the arena of pharmacogenetics/genomics has shed more light on cancer related symptoms such as pain and related them to the cytokine pathways, especially the interleukins and tumor necrosis factor (TNF). When we remember that the synonym for TNF is "cachectin" it is no wonder patients feel awful when there is active disease and the body trying to mount a response. Neuroendocrine, immunomodulatory and inflammatory pathways are likely important in the pathophysiology of pain and depression. These realizations are in addition to a greater understanding of afferent pathways for pain perception, of the multiple opioid receptors, the effects of hormones and catechol metabolism and other transmitters. Moreover we already have a more complete under-standing of drug metabolism, especially of the opioids, the back bone of all pain treatment. There are a number of single nucleotide polymorphisms (SNPs) in the genes important for drug metabolism such as CYP2D6, a cytochrome responsible for about 25% of all drugs. There are about 90 variants already reported and rapid and slow metabolizers need very different doses of codeine or morphine. We are entering an era of having the capability to develop personalized treatment for our patients nociceptive pain, neuropathic pain and depression. The convergence of new knowledge in the molecular

The National Research and Education Network (NREN): Research and Policy Perspectives.

ERIC Educational Resources Information Center

McClure, Charles R.; And Others

This book provides an overview and status report on the progress made in developing the National Research and Education Network (NREN) as of early 1991. It reports on a number of investigations that provide a research and policy perspective on the NREN and computer-mediated communication (CMC), and brings together key source documents that have…

An RDF/OWL knowledge base for query answering and decision support in clinical pharmacogenetics.

PubMed

Samwald, Matthias; Freimuth, Robert; Luciano, Joanne S; Lin, Simon; Powers, Robert L; Marshall, M Scott; Adlassnig, Klaus-Peter; Dumontier, Michel; Boyce, Richard D

2013-01-01

Genetic testing for personalizing pharmacotherapy is bound to become an important part of clinical routine. To address associated issues with data management and quality, we are creating a semantic knowledge base for clinical pharmacogenetics. The knowledge base is made up of three components: an expressive ontology formalized in the Web Ontology Language (OWL 2 DL), a Resource Description Framework (RDF) model for capturing detailed results of manual annotation of pharmacogenomic information in drug product labels, and an RDF conversion of relevant biomedical datasets. Our work goes beyond the state of the art in that it makes both automated reasoning as well as query answering as simple as possible, and the reasoning capabilities go beyond the capabilities of previously described ontologies.

Relevance of pharmacogenetic aspects of mercaptopurine metabolism in the treatment of interstitial lung disease.

PubMed

Bakker, Jaap A; Drent, Marjolein; Bierau, Jörgen

2007-09-01

Mercaptopurine therapy is increasingly important as immunosuppressive therapy in interstitial lung disease. We focus on human mercaptopurine metabolism and the defects in this metabolism causing adverse drug reactions. Defects in mercaptopurine metabolizing enzymes like thiopurine methyltransferase and inosine triphosphate pyrophosphohydrolase lead to severe adverse drug reactions, sometimes with fatal outcome. Other enzymes, still not thoroughly investigated, can give rise to toxic effects or decreased efficacy in mercaptopurine therapy when the activity of these enzymes is altered. Pharmacogenetic screening of potential patients for mercaptopurine therapy is important to avoid adverse drug reactions caused by inherited enzyme deficiencies in these metabolic pathways. Pretreatment screening for deficiencies of mercaptopurine metabolizing enzymes will significantly reduce the number of patients with an adverse drug reaction and concomitantly associated healthcare costs.

Obstetric therapeutics-how pharmacogenetics may inform drug therapy for pregnant women in the future.

PubMed

Haas, David M

2013-09-01

Most pregnant women take prescription medications. There are many factors related to pregnancy that make finding the most effective and safe dose of a therapeutic drug difficult for providers. Genetic differences in drug-metabolizing enzymes, transporters, and receptors may also account for some of the differences in drug response. Single-nucleotide polymorphisms in drug-metabolizing enzymes, such as the cytochrome P450 families, have been studied in relation to drugs used in pregnancy. Combining clinical characteristics, physiologic parameters in pregnancy, and possibly pharmacogenetic models may allow for providers to individualize pharmacotherapy in pregnancy and get to the most effective and safe dose of medication more quickly than in the current practice model. This article discusses these issues along with helpful Web sites and references for providers.

The Use and Significance of a Research Networking System

PubMed Central

Yuan, Leslie; Daigre, John; Meeks, Eric; Nelson, Katie; Piontkowski, Cynthia; Reuter, Katja; Sak, Rachael; Turner, Brian; Weber, Griffin M; Chatterjee, Anirvan

2014-01-01

Background Universities have begun deploying public Internet systems that allow for easy search of their experts, expertise, and intellectual networks. Deployed first in biomedical schools but now being implemented more broadly, the initial motivator of these research networking systems was to enable easier identification of collaborators and enable the development of teams for research. Objective The intent of the study was to provide the first description of the usage of an institutional research “social networking” system or research networking system (RNS). Methods Number of visits, visitor location and type, referral source, depth of visit, search terms, and click paths were derived from 2.5 years of Web analytics data. Feedback from a pop-up survey presented to users over 15 months was summarized. Results RNSs automatically generate and display profiles and networks of researchers. Within 2.5 years, the RNS at the University of California, San Francisco (UCSF) achieved one-seventh of the monthly visit rate of the main longstanding university website, with an increasing trend. Visitors came from diverse locations beyond the institution. Close to 75% (74.78%, 208,304/278,570) came via a public search engine and 84.0% (210 out of a sample of 250) of these queried an individual’s name that took them directly to the relevant profile page. In addition, 20.90% (214 of 1024) visits went beyond the page related to a person of interest to explore related researchers and topics through the novel and networked information provided by the tool. At the end of the period analyzed, more than 2000 visits per month traversed 5 or more links into related people and topics. One-third of visits came from returning visitors who were significantly more likely to continue to explore networked people and topics (P<.001). Responses to an online survey suggest a broad range of benefits of using the RNS in supporting the research and clinical mission. Conclusions Returning

Unified Research on Network-Based Hard/Soft Information Fusion

DTIC Science & Technology

2016-02-02

types). There are a number of search tree run parameters which must be set depending on the experimental setting. A pilot study was run to identify...Unlimited Final Report: Unified Research on Network-Based Hard/Soft Information Fusion The views, opinions and/or findings contained in this report...Final Report: Unified Research on Network-Based Hard/Soft Information Fusion Report Title The University at Buffalo (UB) Center for Multisource

Summit of the Research Coordination Networks for Undergraduate Biology Education

PubMed Central

Eaton, Carrie Diaz; Allen, Deborah; Anderson, Laurel J.; Bowser, Gillian; Pauley, Mark A.; Williams, Kathy S.; Uno, Gordon E.

2016-01-01

The first summit of projects funded by the National Science Foundation’s Research Coordination Networks for Undergraduate Biology Education (RCN-UBE) program was held January 14–16, 2016, in Washington, DC. Sixty-five scientists and science educators from 38 of the 41 Incubator and Full RCN-UBE awards discussed the value and contributions of RCNs to the national biology education reform effort. The summit illustrated the progress of this innovative UBE track, first awarded in 2009. Participants shared experiences regarding network development and growth, identified best practices and challenges faced in network management, and discussed work accomplished. We report here on key aspects of network evaluation, characteristics of successful networks, and how to sustain and broaden participation in networks. Evidence from successful networks indicates that 5 years (the length of a Full RCN-UBE) may be insufficient time to produce a cohesive and effective network. While online communication promotes the activities of a network and disseminates effective practices, face-to-face meetings are critical for establishing ties between network participants. Creation of these National Science Foundation–funded networks may be particularly useful for consortia of faculty working to address problems or exchange novel solutions discovered while introducing active-learning methods and/or course-based research into their curricula.

The role of pharmacogenetics and advances in gene therapy in the treatment of diabetic retinopathy.

PubMed

Agarwal, Aniruddha; Ingham, Sally A; Harkins, Keegan A; Do, Diana V; Nguyen, Quan Dong

2016-02-01

Diabetic retinopathy (DR) and its complications such as diabetic macular edema continue to remain a major cause for legal blindness in the developed world. While the introduction of anti-tVEGF agents has significantly improved visual outcomes of patients with DR, unpredictable response, largely due to genetic polymorphisms, appears to be a challenge with this therapy. With advances in identification of various genetic biomarkers, novel therapeutic strategies consisting of gene transfer are being developed and tested for patients with DR. Application of pharmacogenetic principles appears to be a promising futuristic strategy to attenuate diabetes-mediated retinal vasculopathy. In this comprehensive review, data from recent studies in the field of pharmacogenomics for the treatment of DR have been provided.

The Utrecht Pharmacy Practice network for Education and Research: a network of community and hospital pharmacies in the Netherlands.

PubMed

Koster, Ellen S; Blom, Lyda; Philbert, Daphne; Rump, Willem; Bouvy, Marcel L

2014-08-01

Practice-based networks can serve as effective mechanisms for the development of the profession of pharmacists, on the one hand by supporting student internships and on the other hand by collection of research data and implementation of research outcomes among public health practice settings. This paper presents the characteristics and benefits of the Utrecht Pharmacy Practice network for Education and Research, a practice based research network affiliated with the Department of Pharmaceutical Sciences of Utrecht University. Yearly, this network is used to realize approximately 600 student internships (in hospital and community pharmacies) and 20 research projects. To date, most research has been performed in community pharmacy and research questions frequently concerned prescribing behavior or adherence and subjects related to uptake of regulations in the pharmacy setting. Researchers gain access to different types of data from daily practice, pharmacists receive feedback on the functioning of their own pharmacy and students get in depth insight into pharmacy practice.

The long term agroecosystem research network - shared research strategy

Treesearch

Jean L. Steiner; Timothy Strickland; Peter J.A. Kleinman; Kris Havstad; Thomas B. Moorman; M.Susan Moran; Phil Hellman; Ray B. Bryant; David Huggins; Greg McCarty

2016-01-01

While current weather patterns and rapidly accelerated changes in technology often focus attention on short-term trends in agriculture, the fundamental demands on modern agriculture to meet society food, feed, fuel and fiber production while providing the foundation for a healthy environment requires long-term perspective. The Long- Term Agroecoystem Research Network...

Togetherness, Teamwork and Challenges: "Reflections on Building an Inclusive Research Network"

ERIC Educational Resources Information Center

Riches, Tanya N.; O'Brien, Patricia M.

2017-01-01

Background: This article presents a case study of the Centre for Disability Studies' Inclusive Research Network. The network is a dynamic group of around fifteen people who have intellectual and other disabilities, support workers and university researchers. Methods: The study was based upon an evaluation of the group's research practice, as…

Nation-wide primary healthcare research network: a privacy protection assessment.

PubMed

De Clercq, Etienne; Van Casteren, Viviane; Bossuyt, Nathalie; Moreels, Sarah; Goderis, Geert; Bartholomeeusen, Stefaan; Bonte, Pierre; Bangels, Marc

2012-01-01

Efficiency and privacy protection are essential when setting up nationwide research networks. This paper investigates the extent to which basic services developed to support the provision of care can be re-used, whilst preserving an acceptable privacy protection level, within a large Belgian primary care research network. The generic sustainable confidentiality management model used to assess the privacy protection level of the selected network architecture is described. A short analysis of the current architecture is provided. Our generic model could also be used in other countries.

Multipath Routing in Wireless Sensor Networks: Survey and Research Challenges

PubMed Central

Radi, Marjan; Dezfouli, Behnam; Bakar, Kamalrulnizam Abu; Lee, Malrey

2012-01-01

A wireless sensor network is a large collection of sensor nodes with limited power supply and constrained computational capability. Due to the restricted communication range and high density of sensor nodes, packet forwarding in sensor networks is usually performed through multi-hop data transmission. Therefore, routing in wireless sensor networks has been considered an important field of research over the past decade. Nowadays, multipath routing approach is widely used in wireless sensor networks to improve network performance through efficient utilization of available network resources. Accordingly, the main aim of this survey is to present the concept of the multipath routing approach and its fundamental challenges, as well as the basic motivations for utilizing this technique in wireless sensor networks. In addition, we present a comprehensive taxonomy on the existing multipath routing protocols, which are especially designed for wireless sensor networks. We highlight the primary motivation behind the development of each protocol category and explain the operation of different protocols in detail, with emphasis on their advantages and disadvantages. Furthermore, this paper compares and summarizes the state-of-the-art multipath routing techniques from the network application point of view. Finally, we identify open issues for further research in the development of multipath routing protocols for wireless sensor networks. PMID:22368490

Multipath routing in wireless sensor networks: survey and research challenges.

PubMed

Radi, Marjan; Dezfouli, Behnam; Abu Bakar, Kamalrulnizam; Lee, Malrey

2012-01-01

A wireless sensor network is a large collection of sensor nodes with limited power supply and constrained computational capability. Due to the restricted communication range and high density of sensor nodes, packet forwarding in sensor networks is usually performed through multi-hop data transmission. Therefore, routing in wireless sensor networks has been considered an important field of research over the past decade. Nowadays, multipath routing approach is widely used in wireless sensor networks to improve network performance through efficient utilization of available network resources. Accordingly, the main aim of this survey is to present the concept of the multipath routing approach and its fundamental challenges, as well as the basic motivations for utilizing this technique in wireless sensor networks. In addition, we present a comprehensive taxonomy on the existing multipath routing protocols, which are especially designed for wireless sensor networks. We highlight the primary motivation behind the development of each protocol category and explain the operation of different protocols in detail, with emphasis on their advantages and disadvantages. Furthermore, this paper compares and summarizes the state-of-the-art multipath routing techniques from the network application point of view. Finally, we identify open issues for further research in the development of multipath routing protocols for wireless sensor networks.

Promoting Cognitive Health: A Formative Research Collaboration of the Healthy Aging Research Network

ERIC Educational Resources Information Center

Laditka, James N.; Beard, Renee L.; Bryant, Lucinda L.; Fetterman, David; Hunter, Rebecca; Ivey, Susan; Logsdon, Rebecca G.; Sharkey, Joseph R.; Wu, Bei

2009-01-01

Purpose: Evidence suggests that healthy lifestyles may help maintain cognitive health. The Prevention Research Centers Healthy Aging Research Network, 9 universities collaborating with their communities and the Centers for Disease Control and Prevention, is conducting a multiyear research project, begun in 2005, to understand how to translate this…

Reflections from organization science on the development of primary health care research networks.

PubMed

Fenton, E; Harvey, J; Griffiths, F; Wild, A; Sturt, J

2001-10-01

In the UK, policy changes in primary health care research and development have led to the establishment of primary care research networks. These organizations aim to increase research culture, capacity and evidence base in primary care. As publicly funded bodies, these networks need to be accountable. Organizational science has studied network organizations including why and how they develop and how they function most effectively. This paper draws on organizational science to reflect on why primary care research networks appear to be appropriate for primary care research and how their structures and processes can best enable the achievement of their aims.

Community pharmacists' experience with pharmacogenetic testing.

PubMed

Moaddeb, Jivan; Mills, Rachel; Haga, Susanne B

2015-01-01

Appendix 1 Statements of knowledge of correct medication use Appendix 2 Statements of self-efficacy of correct medication use Appendix 3 Statements of skills of correct medication use To characterize the experiences and feasibility of offering pharmacogenetic (PGx) testing in a community pharmacy setting. Pharmacists were invited to complete a survey about PGx testing for each patient who was offered testing. If the patient consented, pharmacists were also asked to complete a follow-up survey about the process of returning PGx testing results to patients and follow-up with the prescribing provider. Community pharmacies in North Carolina from August through November 2014. Pharmacists at five community pharmacies. Patient consent for testing, time to introduce PGx testing initially and communicate results, interpretation of test results, and recommended medication changes. Of the 69 patients offered testing, 56 (81%) consented. Pre-test counseling typically lasted 1-5 minutes (81%), and most patients (55%) did not have any questions about the testing. Most pharmacists reported test results to patients by phone (84%), with discussions taking less than 1 minute (48%) or 1-5 minutes (52%). Most pharmacists believed the patients understood their results either very well (54%) or somewhat well (41%). Pharmacists correctly interpreted 47 of the 53 test results (89%). All of the incorrect interpretations were for patients with test results indicating a dosing or drug change (6/19; 32%). Pharmacists reported contacting the ordering physician for four patients to discuss results indicating a dosage or drug change. The provision of PGx services in a community pharmacy setting appears feasible, requiring little additional time from the pharmacist, and many patients seem interested in PGx testing. Additional training may be necessary to improve test result interpretation, as well as for communication with both patients and ordering physicians.

Principles and Policies for International Coordination of Research Data Networks

NASA Astrophysics Data System (ADS)

Parsons, M. A.; Mokrane, M.; Sorvari, S.; Treloar, A.; Smith, C.

2017-12-01

International data networks enable the sharing of data within and between scientific disciplines and countries and thus provide the foundation for Open Science. Developing effective and sustainable international research data networks is critical for progress in many areas of research and for science to address complex global societal challenges. However, the development and maintenance of effective networks is not always easy, particularly in a context where public resources for science are limited and international cooperation is not a priority for many countries. The global landscape for data sharing in science is complex; many international data networks already exist and have highly variable structures. Some are linked to large intergovernmental research infrastructures, have highly developed centralized services and deal mainly with the data needs of single disciplines. Some are highly distributed, have much less rigid governance structures and provide access to data from many different domains. Most are somewhere between these two extremes and they cover different geographic regions, from regional to global. All provide a mix of data and associated data services which meets the needs of the research community to various extents and this provision depends on a mix of hardware, software, standards and protocols and human skills. These come together, working across national boundaries, in technical and social networks. In all of this, what makes a network function effectively or not is unclear. This means that there is also no simple answer to what can usefully be done at the policy level to promote the development of effective and sustainable data networks. Hence the rational for the present project - to study a variety of currently successful networks, explore the challenges that they are facing and the lessons that can be learned from confronting these challenges, and, where applicable, to translate this analysis into potential policy actions. Detailed

Primary care research conducted in networks: getting down to business.

PubMed

Mold, James W

2012-01-01

This seventh annual practice-based research theme issue of the Journal of the American Board of Family Medicine highlights primary care research conducted in practice-based research networks (PBRNs). The issue includes discussion of (1) theoretical and methodological research, (2) health care research (studies addressing primary care processes), (3) clinical research (studies addressing the impact of primary care on patients), and (4) health systems research (studies of health system issues impacting primary care including the quality improvement process). We had a noticeable increase in submissions from PBRN collaborations, that is, studies that involved multiple networks. As PBRNs cooperate to recruit larger and more diverse patient samples, greater generalizability and applicability of findings lead to improved primary care processes.

[Training of institutional research networks as a strategy of improvement].

PubMed

Galván-Plata, María Eugenia; Almeida-Gutiérrez, Eduardo; Salamanca-Gómez, Fabio Abdel

2017-01-01

The Instituto Mexicano del Seguro Social (IMSS) through the Coordinación de Investigación en Salud (Health Research Council) has promoted a strong link between the generation of scientific knowledge and the clinical care through the program Redes Institucionales de Investigación (Institutional Research Network Program), whose main aim is to promote and generate collaborative research between clinical, basic, epidemiologic, educational, economic and health services researchers, seeking direct benefits for patients, as well as to generate a positive impact on institutional processes. All of these research lines have focused on high-priority health issues in Mexico. The IMSS internal structure, as well as the sufficient health services coverage, allows the integration of researchers at the three levels of health care into these networks. A few years after their creation, these networks have already generated significant results, and these are currently applied in the institutional regulations in diseases that represent a high burden to health care. Two examples are the National Health Care Program for Patients with Acute Myocardial Infarction "Código Infarto", and the Early Detection Program on Chronic Kidney Disease; another result is the generation of multiple scientific publications, and the promotion of training of human resources in research from the same members of our Research Networks. There is no doubt that the Coordinación de Investigación en Salud advances steadily implementing the translational research, which will keep being fruitful to the benefit of our patients, and of our own institution.

A multiple case study of intersectoral public health networks: experiences and benefits of using research.

PubMed

Kothari, Anita; McPherson, Charmaine; Gore, Dana; Cohen, Benita; MacDonald, Marjorie; Sibbald, Shannon L

2016-02-11

Network partnerships between public health and third sector organisations are being used to address the complexities of population level social determinants of health and health equity. An understanding of how these networks use research and knowledge is crucial to effective network design and outcome evaluation. There is, however, a gap in the literature regarding how public health networks use research and knowledge. The purpose of this paper is to report on the qualitative findings from a larger study that explored (1) the experiences of public health networks with using research and knowledge, and (2) the perceived benefits of using research and knowledge. A multiple case study approach framed this study. Focus group data were collected from participants through a purposive sample of four public health networks. Data were analyzed using Framework Analysis and Nvivo software supported data management. Each network had the opportunity to participate in data interpretation. All networks used published research studies and other types of knowledge to accomplish their work, although in each network research and knowledge played different but complementary roles. Neither research nor other types of knowledge were privileged, and an approach that blended varied knowledge types was typically used. Network experiences with research and knowledge produced individual and collective benefits. A novel finding was that research and knowledge were both important in shaping network function. This study shifts the focus in the current literature from public health departments to the community setting where public health collaborates with a broader spectrum of actors to ameliorate health inequities. Both formal research and informal knowledge were found to be important for collaborative public health networks. Examining the benefits of research and knowledge use within public health networks may help us to better understand the relationships among process (the collaborative use

US Forest Service Experimental Forests and Ranges Network: a continental research platform for catchment-scale research

Treesearch

Daniel Neary; Deborah Hayes; Lindsey Rustad; James Vose; Gerald Gottfried; Stephen Sebesteyn; Sherri Johnson; Fred Swanson; Mary Adams

2012-01-01

The US Forest Service initiated its catchment research program in 1909 with the first paired catchment study at Wagon Wheel Gap, Colorado, USA. It has since developed the Experimental Forests and Ranges Network, with over 80 long-term research study sites located across the contiguous USA, Alaska, Hawaii, and the Caribbean. This network provides a unique, powerful...

Graduate students navigating social-ecological research: insights from the Long-Term Ecological Research Network

Treesearch

Sydne Record; Paige F. B. Ferguson; Elise Benveniste; Rose A. Graves; Vera W. Pfeiffer; Michele Romolini; Christie E. Yorke; Ben Beardmore

2016-01-01

Interdisciplinary, collaborative research capable of capturing the feedbacks between biophysical and social systems can improve the capacity for sustainable environmental decision making. Networks of researchers provide unique opportunities to foster social-ecological inquiry. Although insights into interdisciplinary research have been discussed elsewhere,...

The Influence of Cytochrome P450 Pharmacogenetics on Disposition of Common Antidepressant and Antipsychotic Medications

PubMed Central

van der Weide, Jan; Hinrichs, John WJ

2006-01-01

Since the identification of all the major drug-metabolising cytochrome P450 (CYP) enzymes and their major gene variants, pharmacogenetics has had a major impact on psychotherapeutic drug therapy. CYP enzymes are responsible for the metabolism of most clinically used drugs. Individual variability in CYP activity is an important reason for drug therapy failure. Variability in CYP activity may be caused by various factors, including endogenous factors such as age, gender and morbidity as well as exogenous factors such as co-medication, food components and smoking habit. However, polymorphisms, present in most CYP genes, are responsible for a substantial part of this variability. Although CYP genotyping has been shown to predict the majority of aberrant phenotypes, it is currently rarely performed in clinical practice. PMID:16886044

A data protection scheme for medical research networks. Review after five years of operation.

PubMed

Helbing, K; Demiroglu, S Y; Rakebrandt, F; Pommerening, K; Rienhoff, O; Sax, U

2010-01-01

The data protection requirements matured in parallel to new clinical tests generating more personal data since the 1960s. About ten years ago it was recognized that a generic data protection scheme for medical research networks is required, which reinforces patient rights but also allows economically feasible medical research compared to "hand-carved" individual solutions. To give recommendations for more efficient IT infrastructures for medical research networks in compliance with data protection requirements. The IT infrastructures of three medical research networks were reviewed with respect to the relevant data management modules. Recommendations are derived to increase cost efficiency in research networks assessing the consequences of a service provider approach without lowering the data protection level. The existing data protection schemes are very complex. Smaller research networks cannot afford the implementation of such schemes. Larger networks struggle to keep them sustainable. Due to a modular redesign in the medical research network community, a new approach offers opportunities for an efficient sustainable IT infrastructure involving a service provider concept. For standard components 70-80% of the costs could be cut down, for open source components about 37% over a three-year period. Future research networks should switch to a service-oriented approach to achieve a sustainable, cost-efficient IT infrastructure.

Network cyberinfrastructure as a shared platform to support multi-site research

USDA-ARS?s Scientific Manuscript database

Multi-site research across the Long-term Agroecosystem Research (LTAR) network requires access to data and information. We present some existing examples where you can get data from across the network and summarize the rich inventory of measurements taken across LTAR sites. But data management suppo...

The Southeast Asian Influenza Clinical Research Network: development and challenges for a new multilateral research endeavor.

PubMed

Higgs, Elizabeth S; Hayden, Frederick G; Chotpitayasunondh, Tawee; Whitworth, Jimmy; Farrar, Jeremy

2008-04-01

The Southeast Asia Influenza Clinical Research Network (SEA ICRN) (www.seaclinicalresearch.org) is a recently developed multilateral, collaborative partnership that aims to advance scientific knowledge and management of human influenza through integrated clinical investigation. The partnership of hospitals and institutions in Indonesia, Thailand, United Kingdom, United States, and Viet Nam was established in late 2005 after agreement on the general principles and mission of the initiative and after securing initial financial support. The establishment of the SEA ICRN was both a response to the re-emergence of the highly pathogenic avian influenza A(H5N1) virus in Southeast Asia in late 2003 and an acknowledgment that clinical trials on emerging infectious diseases require prepared and coordinated research capacity. The objectives of the Network also include building sustainable research capacity in the region, compliance with international standards, and prompt dissemination of information and sharing of samples. The scope of research includes diagnosis, pathogenesis, treatment and prevention of human influenza due to seasonal or novel viruses. The Network has overcome numerous logistical and scientific challenges but has now successfully initiated several clinical trials. The establishment of a clinical research network is a vital part of preparedness and an important element during an initial response phase to a pandemic.

Research in Network Management Techniques for Tactical Data Communications Networks.

DTIC Science & Technology

1982-09-01

COMPUTER COMMUNICATIONS US A.RMY (CECOM) V September 1980 to August 1982 Principal Investigatoi Robert Boorstyn Aaron Kershenbaum DTIC Basil Niaglaris Philip...COMMUNICATIONS US ARMY (CECOM) September 1980 to August 1982 Principal Investigators: Robert Boorstyn Aaron Kershenbaum Basil Maglaris Philip Sarachik...TABLE OF CONTENTS Summary of Report Personnel Activities Research Reports / , A. Packet Radio Networks A.1 Throughput Analysis of Multihop Packet

The Wisconsin Network for Health Research (WiNHR): a statewide, collaborative, multi-disciplinary, research group.

PubMed

Bailey, Howard; Agger, William; Baumgardner, Dennis; Burmester, James K; Cisler, Ron A; Evertsen, Jennifer; Glurich, Ingrid; Hartman, David; Yale, Steven H; DeMets, David

2009-12-01

In response to the goals of the Wisconsin Partnership Program and the National Institutes of Health (NIH) Initiatives to Improve Healthcare, the Wisconsin Network for Health Research (WiNHR) was formed. As a collaborative, multi-disciplinary statewide research network, WiNHR encourages and fosters the discovery and application of scientific knowledge for researchers and practitioners throughout Wisconsin. The 4 founding institutions--Aurora Health Care/Center for Urban Population Health (CUPH), Gundersen Lutheran Medical Foundation, Marshfield Clinic Research Foundation, and the University of Wisconsin-Madison--representing geographically diverse areas of the state, are optimistic and committed to WiNHR's success. This optimism is based on the relevance of its goals to public health, the quality of statewide health care research, and, most importantly, the residents of Wisconsin who recognize the value of health research.

The cooperative forestry research unit Commercial Thinning Research Network--9-year results

Treesearch

Robert S. Seymour; Spencer R. Meyer; Robert G. Wagner

2014-01-01

The Commercial Thinning Research Network (CTRN) was established throughout the spruce-fir forest of Maine beginning in 2000 with substantial funding from the University of Maine's Cooperative Forestry Research Unit. One of six replicates of the precommercially thinned stand condition in the CTRN is located in compartment 23A in the U.S. Department of Agriculture,...

A network approach for distinguishing ethical issues in research and development.

PubMed

Zwart, Sjoerd D; van de Poel, Ibo; van Mil, Harald; Brumsen, Michiel

2006-10-01

In this paper we report on our experiences with using network analysis to discern and analyse ethical issues in research into, and the development of, a new wastewater treatment technology. Using network analysis, we preliminarily interpreted some of our observations in a Group Decision Room (GDR) session where we invited important stakeholders to think about the risks of this new technology. We show how a network approach is useful for understanding the observations, and suggests some relevant ethical issues. We argue that a network approach is also useful for ethical analysis of issues in other fields of research and development. The abandoning of the overarching rationality assumption, which is central to network approaches, does not have to lead to ethical relativism.

Establishing a Practice-Based Research Network: Lessons from the Massachusetts Experience

ERIC Educational Resources Information Center

Pulcini, Joyce; Sheetz, Anne; DeSisto, Marie

2008-01-01

This article describes the recently established Massachusetts School Nurse Research Network (MASNRN) which has a mission of establishing a practice-based research network (PBRN) comprised of a representative, collaborative group of professional school nurses, nurse academicians, and other interested parties for whom school health is a priority.…

Network Science Research Laboratory (NSRL) Discrete Event Toolkit

DTIC Science & Technology

2016-01-01

ARL-TR-7579 ● JAN 2016 US Army Research Laboratory Network Science Research Laboratory (NSRL) Discrete Event Toolkit by...Laboratory (NSRL) Discrete Event Toolkit by Theron Trout and Andrew J Toth Computational and Information Sciences Directorate, ARL...Research Laboratory (NSRL) Discrete Event Toolkit 5a. CONTRACT NUMBER 5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) Theron Trout

The Integrated Distributed Virtual Research Network: An Introduction

DTIC Science & Technology

2014-06-01

Tom Kile , Theron Trout, and Gary Cohn for their extensive contribution to this document to include reviews, comments, and edits, which contributed...to the quality of the document. The ARL Integrated Distributed Virtual Research Testbed (IDVRT) team, consisting of Alex Tarantin, Khoa Bui, Tom Kile ...n. Network Engineer (non-voting member) Tom Kile o. Network Engineer (non-voting member) Theron Trout p. Non-voting members (serving at the

The National Wind Erosion Research Network: Building a standardized long-term data resource for aeolian research, modeling and land management

USGS Publications Warehouse

Webb, Nicholas P.; Herrick, Jeffrey E.; Van Zee, Justin W; Courtright, Ericha M; Hugenholtz, Ted M; Zobeck, Ted M; Okin, Gregory S.; Barchyn, Thomas E; Billings, Benjamin J; Boyd, Robert A.; Clingan, Scott D; Cooper, Brad F; Duniway, Michael C.; Derner, Justin D.; Fox, Fred A; Havstad, Kris M.; Heilman, Philip; LaPlante, Valerie; Ludwig, Noel A; Metz, Loretta J; Nearing, Mark A; Norfleet, M Lee; Pierson, Frederick B; Sanderson, Matt A; Sharrat, Brenton S; Steiner, Jean L; Tatarko, John; Tedela, Negussie H; Todelo, David; Unnasch, Robert S; Van Pelt, R Scott; Wagner, Larry

2016-01-01

The National Wind Erosion Research Network was established in 2014 as a collaborative effort led by the United States Department of Agriculture’s Agricultural Research Service and Natural Resources Conservation Service, and the United States Department of the Interior’s Bureau of Land Management, to address the need for a long-term research program to meet critical challenges in wind erosion research and management in the United States. The Network has three aims: (1) provide data to support understanding of basic aeolian processes across land use types, land cover types, and management practices, (2) support development and application of models to assess wind erosion and dust emission and their impacts on human and environmental systems, and (3) encourage collaboration among the aeolian research community and resource managers for the transfer of wind erosion technologies. The Network currently consists of thirteen intensively instrumented sites providing measurements of aeolian sediment transport rates, meteorological conditions, and soil and vegetation properties that influence wind erosion. Network sites are located across rangelands, croplands, and deserts of the western US. In support of Network activities, http://winderosionnetwork.org was developed as a portal for information about the Network, providing site descriptions, measurement protocols, and data visualization tools to facilitate collaboration with scientists and managers interested in the Network and accessing Network products. The Network provides a mechanism for engaging national and international partners in a wind erosion research program that addresses the need for improved understanding and prediction of aeolian processes across complex and diverse land use types and management practices.

Proposed Development of NASA Glenn Research Center's Aeronautical Network Research Simulator

NASA Technical Reports Server (NTRS)

Nguyen, Thanh C.; Kerczewski, Robert J.; Wargo, Chris A.; Kocin, Michael J.; Garcia, Manuel L.

2004-01-01

Accurate knowledge and understanding of data link traffic loads that will have an impact on the underlying communications infrastructure within the National Airspace System (NAS) is of paramount importance for planning, development and fielding of future airborne and ground-based communications systems. Attempting to better understand this impact, NASA Glenn Research Center (GRC), through its contractor Computer Networks & Software, Inc. (CNS, Inc.), has developed an emulation and test facility known as the Virtual Aircraft and Controller (VAC) to study data link interactions and the capacity of the NAS to support Controller Pilot Data Link Communications (CPDLC) traffic. The drawback of the current VAC test bed is that it does not allow the test personnel and researchers to present a real world RF environment to a complex airborne or ground system. Fortunately, the United States Air Force and Navy Avionics Test Commands, through its contractor ViaSat, Inc., have developed the Joint Communications Simulator (JCS) to provide communications band test and simulation capability for the RF spectrum through 18 GHz including Communications, Navigation, and Identification and Surveillance functions. In this paper, we are proposing the development of a new and robust test bed that will leverage on the existing NASA GRC's VAC and the Air Force and Navy Commands JCS systems capabilities and functionalities. The proposed NASA Glenn Research Center's Aeronautical Networks Research Simulator (ANRS) will combine current Air Traffic Control applications and physical RF stimulation into an integrated system capable of emulating data transmission behaviors including propagation delay, physical protocol delay, transmission failure and channel interference. The ANRS will provide a simulation/stimulation tool and test bed environment that allow the researcher to predict the performance of various aeronautical network protocol standards and their associated waveforms under varying

Using Action Research and Action Learning for Entrepreneurial Network Capability Development

ERIC Educational Resources Information Center

McGrath, Helen; O'Toole, Thomas

2016-01-01

This paper applies an action research (AR) design and action learning (AL) approach to network capability development in an entrepreneurial context. Recent research suggests that networks are a viable strategy for the entrepreneurial firm to overcome the liabilities associated with newness and smallness. However, a gap emerges as few, if any,…

The USDA Long-Term Agro-ecosystems Research (LTAR) Network

NASA Astrophysics Data System (ADS)

Goodrich, D. C.; Walthall, C. L.; Campbell, J. D.; Derner, J. D.; Huggins, D. R.; Kleinman, P. J. A.; Locke, M. A.; Sadler, J.; Steiner, J. L.; Strickland, T.; Swain, H.

2016-12-01

The USDA-Agricultural Research Service (ARS) has a multi-decadal to century long history of experimental watersheds, ranges and research farms throughout the USA. Many of these ARS research facilities, as well as three led by private foundations or land grant universities, are now part of the USDA Long-Term Agro-ecosystem Research (LTAR) network that currently has 18 locations. These 18 locations encompass a diversity of agricultural systems as well as provide a research platform for regional to national scale assessments and modeling scenarios of ecosystem goods and services for society. A central challenge that LTAR will address is: How can we sustain or enhance agricultural productivity, profitability, and ecosystem services to feed 9 billion people by 2050? Each LTAR location is designing a common experiment that consists of comparing "business as usual" to "aspirational agriculture" management strategies that reflect prevailing local to regional agricultural systems. The "aspirational agriculture" management strategy for each location will be forward-looking with innovative incorporations of cutting-edge technology, social-ecological systems involving human dimensions and economics, ecosystem services such as pollinator habitat and soil health, and paradigm shifting agricultural enterprise transformations. To accomplish the central challenge, LTAR locations will leverage existing historical data with new network-level initiatives such as wind erosion, phenology, water/carbon/nutrient/energy fluxes, complete water balances, greenhouse gas fluxes and remote sensing/modeling efforts to determine the sustainability of US agriculture across regional to continental scales. This presentation will provide an overview of the current status of the LTAR network, describe several common experiments, showcase the data management systems and web presentations of this data, as well as recent network findings.

The Wisconsin Network for Health Research (WiNHR): A Statewide, Collaborative, Multi-disciplinary, Research Group

PubMed Central

Bailey, Howard; Agger, William; Baumgardner, Dennis; Burmester, James K.; Cisler, Ron A.; Evertsen, Jennifer; Glurich, Ingrid; Hartman, David; Yale, Steven H.; DeMets, David

2010-01-01

In response to the goals of the Wisconsin Partnership Program and the National Institutes of Health (NIH) Initiatives to Improve Healthcare, the Wisconsin Network for Health Research (WiNHR) was formed. As a collaborative, multi-disciplinary statewide research network, WiNHR encourages and fosters the discovery and application of scientific knowledge for researchers and practitioners throughout Wisconsin. The 4 founding institutions—Aurora Health Care/Center for Urban Population Health (CUPH), Gundersen Lutheran Medical Foundation, Marshfield Clinic Research Foundation, and the University of Wisconsin-Madison—representing geographically diverse areas of the state, are optimistic and committed to WiNHR’s success. This optimism is based on the relevance of its goals to public health, the quality of statewide health care research, and, most importantly, the residents of Wisconsin who recognize the value of health research. PMID:20131687

Pilot study of pharmacist-assisted delivery of pharmacogenetic testing in a primary care setting.

PubMed

Haga, Susanne B; LaPointe, Nancy M Allen; Cho, Alex; Reed, Shelby D; Mills, Rachel; Moaddeb, Jivan; Ginsburg, Geoffrey S

2014-09-01

To describe the rationale and design of a pilot program to implement and evaluate pharmacogenetic (PGx) testing in a primary care setting. Several factors have impeded the uptake of PGx testing, including lack of provider knowledge and challenges with operationalizing PGx testing in a clinical practice setting. We plan to compare two strategies for the implementation of PGx testing: a pharmacist-initiated testing arm compared with a physician-initiated PGx testing arm. Providers in both groups will be required to attend an introduction to PGx seminar. Anticipated results: We anticipate that providers in the pharmacist-initiated group will be more likely to order PGx testing than providers in the physician-initiated group. Overall, we aim to generate data that will inform an effective delivery model for PGx testing and to facilitate a seamless integration of PGx testing in primary care practices.

The Global Research Collaboration of Network Meta-Analysis: A Social Network Analysis

PubMed Central

Li, Lun; Catalá-López, Ferrán; Alonso-Arroyo, Adolfo; Tian, Jinhui; Aleixandre-Benavent, Rafael; Pieper, Dawid; Ge, Long; Yao, Liang; Wang, Quan; Yang, Kehu

2016-01-01

Background and Objective Research collaborations in biomedical research have evolved over time. No studies have addressed research collaboration in network meta-analysis (NMA). In this study, we used social network analysis methods to characterize global collaboration patterns of published NMAs over the past decades. Methods PubMed, EMBASE, Web of Science and the Cochrane Library were searched (at 9th July, 2015) to include systematic reviews incorporating NMA. Two reviewers independently selected studies and cross-checked the standardized data. Data was analyzed using Ucinet 6.0 and SPSS 17.0. NetDraw software was used to draw social networks. Results 771 NMAs published in 336 journals from 3459 authors and 1258 institutions in 49 countries through the period 1997–2015 were included. More than three-quarters (n = 625; 81.06%) of the NMAs were published in the last 5-years. The BMJ (4.93%), Current Medical Research and Opinion (4.67%) and PLOS One (4.02%) were the journals that published the greatest number of NMAs. The UK and the USA (followed by Canada, China, the Netherlands, Italy and Germany) headed the absolute global productivity ranking in number of NMAs. The top 20 authors and institutions with the highest publication rates were identified. Overall, 43 clusters of authors (four major groups: one with 37 members, one with 12 members, one with 11 members and one with 10 members) and 21 clusters of institutions (two major groups: one with 62 members and one with 20 members) were identified. The most prolific authors were affiliated with academic institutions and private consulting firms. 181 consulting firms and pharmaceutical industries (14.39% of institutions) were involved in 199 NMAs (25.81% of total publications). Although there were increases in international and inter-institution collaborations, the research collaboration by authors, institutions and countries were still weak and most collaboration groups were small sizes. Conclusion Scientific

Study of co-authorship network of papers in the Journal of Research in Medical Sciences using social network analysis

PubMed Central

Zare-Farashbandi, Firoozeh; Geraei, Ehsan; Siamaki, Saba

2014-01-01

Background: Co-authorship is one of the most tangible forms of research collaboration. A co-authorship network is a social network in which the authors through participation in one or more publication through an indirect path have linked to each other. The present research using the social network analysis studied co-authorship network of 681 articles published in Journal of Research in Medical Sciences (JRMS) during 2008-2012. Materials and Methods: The study was carried out with the scientometrics approach and using co-authorship network analysis of authors. The topology of the co-authorship network of 681 published articles in JRMS between 2008 and 2012 was analyzed using macro-level metrics indicators of network analysis such as density, clustering coefficient, components and mean distance. In addition, in order to evaluate the performance of each authors and countries in the network, the micro-level indicators such as degree centrality, closeness centrality and betweenness centrality as well as productivity index were used. The UCINET and NetDraw softwares were used to draw and analyze the co-authorship network of the papers. Results: The assessment of the authors productivity in this journal showed that the first ranks were belonged to only five authors, respectively. Furthermore, analysis of the co-authorship of the authors in the network demonstrated that in the betweenness centrality index, three authors of them had the good position in the network. They can be considered as the network leaders able to control the flow of information in the network compared with the other members based on the shortest paths. On the other hand, the key role of the network according to the productivity and centrality indexes was belonged to Iran, Malaysia and United States of America. Conclusion: Co-authorship network of JRMS has the characteristics of a small world network. In addition, the theory of 6° separation is valid in this network was also true. PMID:24672564

Symposium Connects Government Problems with State of the Art Network Science Research

DTIC Science & Technology